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OBJECTIVE: The BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system. DESIGN: A partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values. OUTCOME MEASURES: The effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted. RESULTS: The ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was 69 823/QALY, 70 421/QALY and 72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of 90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively. CONCLUSIONS: This analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.
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Neoplasias del Colon , Neoplasias del Recto , Adulto , Humanos , Cetuximab/uso terapéutico , Análisis Costo-Beneficio , Proteínas Proto-Oncogénicas B-raf/genética , Irinotecán , Bevacizumab/uso terapéutico , Inhibidores de Proteínas Quinasas , FranciaRESUMEN
BACKGROUND: Aliskiren is the first oral direct renin inhibitor to be approved for the treatment of hypertension. The pharmacokinetic and pharmacodynamic profile of aliskiren has been extensively characterized in Caucasian individuals; however, drug disposition, treatment response and tolerability can vary among ethnic groups, and these variations are difficult to predict. OBJECTIVE: To evaluate the single- and multiple-dose pharmacokinetics of aliskiren in healthy Chinese subjects. METHODS: This was a randomized, single-blind, parallel-group, placebo-controlled study. On day -1, subjects were randomized to one of four cohorts (aliskiren 75, 150, 300 or 600 mg). On day 1, eight individuals in each cohort received a single dose of active treatment and two received placebo. Subjects randomized to aliskiren 300 mg received additional once-daily doses on days 5-11 to establish steady-state pharmacokinetics. Subjects receiving aliskiren 75, 150 or 600 mg (cohorts 1, 2 and 4) completed the study at the end of the 96-hour pharmacokinetic assessment period. Subjects receiving aliskiren 300 mg (cohort 3) had additional pharmacokinetic assessments on days 5-15. The study was carried out at the Peking Union Medical College Hospital, Beijing, China, and included 40 healthy Chinese subjects. The main outcome measures were the pharmacokinetic parameters for aliskiren, including area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and maximum plasma concentration (C(max)). RESULTS: Aliskiren AUC(infinity) and C(max) increased greater than proportionally across the 8-fold dose range (75-600 mg; mean AUC(infinity) 291-4726 ng x h/mL, mean C(max) 62-699 ng/mL), but a dose-proportional 2-fold increase was observed within the clinically approved dose range (150-300 mg; mean AUC(infinity) 876-1507 ng x h/mL, mean C(max) 137-271 ng/mL). CONCLUSION: At steady state, the mean AUC during the dosage interval (AUC(tau)) for aliskiren 300 mg (1532 +/- 592 ng x h/mL) was similar to the AUC(infinity) observed following a single dose. Aliskiren exhibits similar single-dose and steady-state pharmacokinetics in Chinese subjects compared with those observed in Caucasian individuals in previous studies.
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Amidas/farmacocinética , Antihipertensivos/farmacocinética , Fumaratos/farmacocinética , Renina/antagonistas & inhibidores , Administración Oral , Adulto , Amidas/administración & dosificación , Amidas/efectos adversos , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Área Bajo la Curva , Pueblo Asiatico , China , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Fumaratos/administración & dosificación , Fumaratos/efectos adversos , Humanos , Masculino , Método Simple Ciego , Adulto JovenRESUMEN
The pharmacokinetics, absorption, metabolism, and excretion of vildagliptin, a potent and orally active inhibitor of dipeptidyl peptidase 4, were evaluated in male rats and dogs. Vildagliptin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45-100%). The distribution and elimination half-lives of vildagliptin were short: 0.57 h [82% of area under the plasma drug concentration-time curve (AUC)] and 8.8 h in the rat and 0.05 and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution was 1.6 and 8.6 l/kg in dogs and rats, respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) compared with their hepatic blood flow. The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog), and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6-72.4%) was the major route of elimination for rats and dogs as 18.9 to 21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81-100% of the dose). Vildagliptin was mainly metabolized before excretion in both species. Similar to plasma, the most predominant metabolite in excreta was M20.7 in rats and dogs, and another major metabolite in dogs was M15.3.
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Adamantano/análogos & derivados , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Adamantano/farmacocinética , Animales , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Perros , Técnicas In Vitro , Masculino , Unión Proteica , Ratas , Ratas Endogámicas F344 , Espectrometría de Masas en Tándem , Distribución Tisular , VildagliptinaRESUMEN
The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [(14)C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.
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Adamantano/análogos & derivados , Radioisótopos de Carbono/farmacocinética , Hipoglucemiantes/farmacocinética , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Absorción , Adamantano/metabolismo , Adamantano/farmacocinética , Área Bajo la Curva , Radioisótopos de Carbono/metabolismo , Cromatografía Líquida de Alta Presión , Inhibidores de la Dipeptidil-Peptidasa IV , Humanos , Hidrólisis , Hipoglucemiantes/metabolismo , Técnicas In Vitro , Espectrometría de Masas , Nitrilos/metabolismo , Unión Proteica , Pirrolidinas/metabolismo , VildagliptinaRESUMEN
Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1-3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47-51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7-8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion. No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability. Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12,000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide [frusemide]), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentration. Moreover, PRA inhibition and BP reductions persist for 2-4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication. Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.
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Amidas/farmacocinética , Antihipertensivos/farmacocinética , Fumaratos/farmacocinética , Hipertensión/tratamiento farmacológico , Administración Oral , Amidas/farmacología , Antihipertensivos/farmacología , Disponibilidad Biológica , Interacciones Farmacológicas , Fumaratos/farmacología , Humanos , Renina/antagonistas & inhibidoresRESUMEN
We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.
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Adamantano/análogos & derivados , Amlodipino/farmacocinética , Antihipertensivos/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Ramipril/análogos & derivados , Tetrazoles/farmacocinética , Valina/análogos & derivados , Adamantano/administración & dosificación , Adamantano/efectos adversos , Adamantano/farmacocinética , Administración Oral , Adulto , Amlodipino/administración & dosificación , Amlodipino/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Área Bajo la Curva , Estudios Cruzados , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Interacciones Farmacológicas , Femenino , Semivida , Cefalea/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Ramipril/administración & dosificación , Ramipril/efectos adversos , Ramipril/farmacocinética , Comprimidos , Tetrazoles/administración & dosificación , Tetrazoles/efectos adversos , Valina/administración & dosificación , Valina/efectos adversos , Valina/farmacocinética , Valsartán , VildagliptinaRESUMEN
This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.
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Amidas/farmacología , Antihipertensivos/farmacología , Electrocardiografía/efectos de los fármacos , Fumaratos/farmacología , Renina/antagonistas & inhibidores , Adulto , Amidas/efectos adversos , Amidas/farmacocinética , Compuestos Aza/farmacología , Método Doble Ciego , Femenino , Fluoroquinolonas , Fumaratos/efectos adversos , Fumaratos/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Quinolinas/farmacologíaRESUMEN
This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Amidas/farmacocinética , Antifúngicos/farmacocinética , Digoxina/farmacocinética , Fumaratos/farmacocinética , Ácidos Heptanoicos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Cetoconazol/farmacocinética , Pirroles/farmacocinética , Renina/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Adulto , Amidas/efectos adversos , Animales , Antifúngicos/efectos adversos , Atorvastatina , Células CACO-2 , Línea Celular , Citocromo P-450 CYP3A/metabolismo , Digoxina/efectos adversos , Interacciones Farmacológicas , Femenino , Fumaratos/efectos adversos , Ácidos Heptanoicos/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Cetoconazol/efectos adversos , Masculino , Transportadores de Anión Orgánico/metabolismo , Pirroles/efectos adversos , Distribución Tisular , Adulto JovenRESUMEN
UNLABELLED: What is already known about this subject. Vildagliptin is a new, potent, and selective inhibitor of DPP-4. The efficacy and safety of vildagliptin in type 2 diabetes has been intensively studied in diverse subject populations. There has been little information published about the pharmacokinetics and pharmacodynamics of vildagliptin. What this study adds. No clinically relevant changes in pharmacokinetics or pharmacodynamics were observed between young and elderly, male and female, or high body mass index (BMI) and low BMI subjects. The results suggest that no dose modification is necessary for vildagliptin based on the age, gender, or BMI of a subject. AIMS: To evaluate the effect of age, gender, and body mass index (BMI) on the pharmacokinetics and pharmacodynamics of vildagliptin. METHODS: Forty healthy subjects received a single oral dose of 100 mg vildagliptin to assess the effects of age, gender, and BMI on the pharmacokinetics and pharmacodynamics, reflected by the time course of inhibition of DPP-4 activity, of vildagliptin. RESULTS: Peak concentration and exposure (AUC((0-infinity))) of vildagliptin were 17% (90% CI 2, 35%) and 31% (90% CI 18, 45%) higher in elderly vs. young subjects. Renal clearance was reduced by 32% (90% CI 17, 45%) in elderly subjects. The pharmacokinetics of vildagliptin were not significantly influenced by gender or BMI. Inhibition of DPP-4 activity was similar regardless of age, gender, or BMI. CONCLUSIONS: The pharmacokinetics of a single oral 100 mg dose of vildagliptin were not affected by gender and BMI. Exposure to vildagliptin was higher in elderly patients, but this was not associated with any difference in the effect of DPP-4 inhibition. Based on these results, no vildagliptin dose adjustment is necessary for age, gender, or BMI.
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Adamantano/análogos & derivados , Envejecimiento/metabolismo , Índice de Masa Corporal , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Caracteres Sexuales , Adamantano/administración & dosificación , Adamantano/farmacocinética , Adamantano/farmacología , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/efectos de los fármacos , Femenino , Humanos , Masculino , Nitrilos/administración & dosificación , Nitrilos/farmacología , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacología , VildagliptinaRESUMEN
BACKGROUND: Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan. METHODS: This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14. RESULTS: Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan. CONCLUSIONS: Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.
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Amidas/farmacocinética , Compuestos de Bifenilo/farmacocinética , Fumaratos/farmacocinética , Enfermedades Renales/tratamiento farmacológico , Tetrazoles/farmacocinética , Administración Oral , Amidas/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Quimioterapia Combinada , Fumaratos/administración & dosificación , Humanos , Irbesartán , Farmacocinética , Renina/antagonistas & inhibidores , Tetrazoles/administración & dosificaciónRESUMEN
BACKGROUND AND OBJECTIVE: Vildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers. METHODS: This was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed. RESULTS: Both noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating 'flip-flop' kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h). CONCLUSIONS: Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.
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Adamantano/análogos & derivados , Inhibidores de la Dipeptidil-Peptidasa IV , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Adamantano/administración & dosificación , Adamantano/farmacocinética , Administración Oral , Adolescente , Adulto , Algoritmos , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Índice de Masa Corporal , Peso Corporal , Estudios Cruzados , Dipeptidil Peptidasa 4 , Femenino , Semivida , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Nitrilos/administración & dosificación , Pirrolidinas/administración & dosificación , Factores Sexuales , VildagliptinaRESUMEN
This open-label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (>or=65 years) and 28 young (18-45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300-mg oral dose of aliskiren. In elderly compared with young subjects, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n=16) and >or=75 years (n=13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.
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Amidas/efectos adversos , Amidas/farmacocinética , Fumaratos/efectos adversos , Fumaratos/farmacocinética , Renina/antagonistas & inhibidores , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Amidas/sangre , Área Bajo la Curva , Femenino , Fumaratos/sangre , Tasa de Filtración Glomerular , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing alpha- and beta-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r(2) = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC(0-infinity) and C(max) but no dose-dependent changes in time to reach C(max) or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased C(max) by 19% and AUC(0-infinity) by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.
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Adamantano/análogos & derivados , Grasas de la Dieta , Inhibidores de la Dipeptidil-Peptidasa IV , Interacciones Alimento-Droga , Hipoglucemiantes/farmacocinética , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Adamantano/administración & dosificación , Adamantano/efectos adversos , Adamantano/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Intervalos de Confianza , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Masculino , Modelos Estadísticos , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , VildagliptinaRESUMEN
Vildagliptin is a novel antidiabetic agent that is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV, the enzyme responsible for degradation of the incretin hormones. This open-label, randomized, 3-period crossover study investigated the potential for pharmacokinetic interactions in 18 healthy subjects during coadministration of vildagliptin and digoxin. Subjects were randomized to receive each of 3 treatments: vildagliptin 100 mg qd, digoxin (0.5 mg, then 0.25 mg qd on days 2-7), and the combination vildagliptin/digoxin for 7 days. Coadministration of digoxin with vildagliptin had no effect on exposure to vildagliptin (geometric mean ratios [90% confidence interval]: AUC(0-24h), 0.99 [0.95-1.03]; C(max), 0.95 [0.85-1.06]) or to digoxin (AUC(0-24h), 1.02 [0.94-1.12]; C(max), 1.08 [0.97-1.20]). In addition, no changes in t(max), t((1/2)), and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.
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Adamantano/análogos & derivados , Antiarrítmicos/farmacocinética , Digoxina/farmacocinética , Hipoglucemiantes/farmacocinética , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Adamantano/efectos adversos , Adamantano/farmacocinética , Adolescente , Adulto , Antiarrítmicos/efectos adversos , Estudios Cruzados , Digoxina/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV , Interacciones Farmacológicas , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Nitrilos/efectos adversos , Pirrolidinas/efectos adversos , VildagliptinaRESUMEN
BACKGROUND AND OBJECTIVE: Telithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (C(max)) over MIC (C(max)/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP). PATIENTS AND METHODS: Data were pooled from five phase III studies of oral telithromycin (800 mg once daily for 7-10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and C(max) Bayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MIC and C(max)/MIC and microbiological outcome by pathogen. RESULTS: The bmITT population included 224 patients (Streptococcus pneumoniae in 113, Haemophilus influenzae in 89 and Staphylococcus aureus in 22). Median telithromycin MIC was 0.015 microg/mL for S. pneumoniae, 2.0 microg/mL for H. influenzae and 0.12 microg/mL for S. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median C(max)/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or C(max)/MIC breakpoints were identified by CART. CONCLUSION: Telithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800 mg once daily.
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Antibacterianos/uso terapéutico , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Cetólidos/uso terapéutico , Neumonía/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Área Bajo la Curva , Teorema de Bayes , Infecciones Comunitarias Adquiridas/microbiología , Femenino , Haemophilus influenzae/efectos de los fármacos , Humanos , Cetólidos/administración & dosificación , Cetólidos/farmacocinética , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Neumonía/microbiología , Staphylococcus aureus/efectos de los fármacos , Estadísticas no Paramétricas , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
Pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1ß monoclonal antibody, canakinumab, in gouty arthritis patients from three studies are reported. Canakinumab has low serum clearance (0.214 L/day), low steady-state volume of distribution (7.44 L), a 25.8-day half-life, and approximately 60% subcutaneous absolute bioavailability in a typical 93-kg patient. Creatinine clearance had a small positive impact on serum canakinumab clearance that is not likely to be clinically relevant. Binding to circulating IL-1ß was demonstrated by increases in total serum IL-1ß following canakinumab dosing. Total IL-1ß kinetics and canakinumab pharmacokinetics were characterized by a population-based pharmacokinetic-binding model, where the estimated apparent in vivo dissociation constant (signifying binding affinity of canakinumab to circulating IL-1ß) was 0.99 nmol/L in gouty arthritis patients. Canakinumab treatment provided rapid, sustained decreases in C-reactive protein and serum amyloid A, provided superior pain relief to triamcinolone acetonide, and increased time to first recurrent attack (P ≤ 0.01 favoring all canakinumab doses vs. triamcinolone acetonide).
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Anticuerpos Monoclonales/farmacología , Artritis Gotosa/metabolismo , Interleucina-1beta/antagonistas & inhibidores , Adulto , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales Humanizados , Artritis Gotosa/tratamiento farmacológico , Proteína C-Reactiva/análisis , Método Doble Ciego , Humanos , Interleucina-1beta/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Proteína Amiloide A Sérica/análisisRESUMEN
Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.
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Amidas/farmacología , Amidas/uso terapéutico , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Peso Corporal , Fumaratos/farmacología , Fumaratos/uso terapéutico , Hipertensión/tratamiento farmacológico , Caracteres Sexuales , Adulto , Amidas/sangre , Amidas/farmacocinética , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Presión Sanguínea/efectos de los fármacos , Composición Corporal , Índice de Masa Corporal , Ensayos Clínicos como Asunto , Femenino , Fumaratos/sangre , Fumaratos/farmacocinética , Humanos , Hipertensión/sangre , Masculino , Renina/antagonistas & inhibidores , Renina/sangreRESUMEN
OBJECTIVE: Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters). RESEARCH DESIGN AND METHODS: Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS. RESULTS: Co-administration of aliskiren with allopurinol had no effect on allopurinol AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (mean ratio 1.08 [90% CI, 1.04, 1.13]), with 90% CI within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (geometric mean ratios 0.88-1.02 with 90% CI including 1.00, but with some 90% CI outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) by 25% (mean ratio 1.25 [90% CI, 0.98, 1.59]). CONCLUSIONS: In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.
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Alopurinol/farmacocinética , Amidas/farmacocinética , Cimetidina/farmacocinética , Fumaratos/farmacocinética , Pirazoles/farmacocinética , Renina/antagonistas & inhibidores , Sulfonamidas/farmacocinética , Adolescente , Adulto , Alopurinol/sangre , Amidas/sangre , Antihipertensivos/farmacocinética , Celecoxib , Cimetidina/sangre , Inhibidores de la Ciclooxigenasa/farmacocinética , Interacciones Farmacológicas , Femenino , Fumaratos/sangre , Supresores de la Gota/farmacocinética , Antagonistas de los Receptores H2 de la Histamina/farmacocinética , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pirazoles/sangre , Valores de Referencia , Sulfonamidas/sangreRESUMEN
OBJECTIVE: Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers. METHODS: In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000 mg (n = 22), pioglitazone 45 mg (n = 30) or fenofibrate 200 mg (n = 21) and aliskiren 300 mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations. RESULTS: Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration- time curve during the dose interval (AUC(tau)) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (C(max)) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUC (GMR 1.05; 90% CI 0.96, 1.16) or C(max) (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUC(tau) (GMR 1.05; 90% CI 0.98, 1.13) or C(max) (GMR 1.01; 90% CI 0.84, 1.20). All other AUC and C(max) GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglita-zone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25. CONCLUSION: Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.
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Amidas/farmacocinética , Antihipertensivos/farmacocinética , Fenofibrato/farmacocinética , Fumaratos/farmacocinética , Metformina/farmacocinética , Renina/antagonistas & inhibidores , Tiazolidinedionas/farmacocinética , Adolescente , Adulto , Amidas/administración & dosificación , Amidas/sangre , Antihipertensivos/administración & dosificación , Antihipertensivos/sangre , Antihipertensivos/farmacología , Área Bajo la Curva , Cromatografía Liquida , Interacciones Farmacológicas , Femenino , Fenofibrato/administración & dosificación , Fenofibrato/sangre , Fumaratos/administración & dosificación , Fumaratos/sangre , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Hipolipemiantes/sangre , Hipolipemiantes/farmacocinética , Masculino , Metformina/administración & dosificación , Metformina/sangre , Persona de Mediana Edad , Pioglitazona , Espectrometría de Masas en Tándem , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/sangreRESUMEN
This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended-release formulation of isosorbide-5-mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18-45 years) received either ISMN 40 mg or furosemide 20 mg once-daily for 3 days followed by a 3-day washout. Subjects then received aliskiren 300 mg once-daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC(tau) was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C(max) by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC(tau) by 28% (0.72 [0.64, 0.81]) and C(max) by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC(tau) 1.03 [0.90, 1.18]; C(max) 0.94 [0.69, 1.29]) and ISMN (AUC(tau) 0.88 [0.71, 1.10]; C(max) 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP < 90 and/or DBP < 50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.