Economic evaluation of encorafenib with cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer in France: a cost-effectiveness analysis using data from the BEACON CRC randomised controlled trial.

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.

Pharmacokinetic and pharmacodynamic properties of canakinumab in patients with gouty arthritis.

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).

Pharmacokinetics, safety and tolerability of single and multiple oral doses of aliskiren in healthy Chinese subjects: a randomized, single-blind, parallel-group, placebo-controlled study.

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.

Influence of body weight and gender on the pharmacokinetics, pharmacodynamics, and antihypertensive efficacy of aliskiren.

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.

Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans.

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.

Disposition of vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in rats and dogs.

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.

Pharmacokinetic interaction of the direct renin inhibitor aliskiren with furosemide and extended-release isosorbide-5-mononitrate in healthy subjects.

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.

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects.

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.

Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren.

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.

Clinical pharmacokinetics and pharmacodynamics of aliskiren.

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.

Effects of aliskiren, a direct Renin inhibitor, on cardiac repolarization and conduction in healthy subjects.

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.

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with allopurinol, celecoxib and cimetidine in healthy subjects.

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.

Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects.

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.

The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteers.

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.

A randomized, crossover study to evaluate the pharmacokinetics of amantadine and oseltamivir administered alone and in combination.

UNLABELLED: The threat of potential pandemic influenza requires a reevaluation of licensed therapies for the prophylaxis or treatment of avian H5N1 infection that may adapt to man. Among the therapies considered for use in pandemic influenza is the co-administration of ion channel and neuraminidase inhibitors, both to potentially increase efficacy as well as to decrease the emergence of resistant isolates. To better understand the potential for drug interactions, a cross-over, randomized, open-label trial was conducted with amantadine, 100 mg po bid, and oseltamivir, 75 mg po bid, given alone or in combination for 5 days. Each subject (N = 17) served as their own control and was administered each drug alone or in combination, with appropriate wash-out. Co-administration with oseltamivir had no clinically significant effect on the pharmacokinetics (PK) of amantadine [mean ratios (90% CI) for AUC(0-12) 0.93 (0.89, 0.98) and C(max) 0.96 (0.90, 1.02)]. Similarly, amantadine co-administration did not affect oseltamivir PK [AUC(0-12) 0.92 (0.86, 0.99) and C(max) 0.85 (0.73, 0.99)] or the PK of the metabolite, oseltamivir carboxylate [AUC(0-12) 0.98 (0.95, 1.02) and C(max) 0.95 (0.89, 1.01)]. In this small trial there was no evidence of an increase in adverse events. Although many more subjects would need to be studied to rule out a synergistic increase in adverse events, the combination in this small human drug-drug interaction trial appears safe and without pharmacokinetic consequences. TRIAL REGISTRATION: ClinicalTrials.gov NCT00416962.

The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers.

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.

Evaluation of pharmacokinetic interactions between vildagliptin and digoxin in healthy volunteers.

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.

Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment.

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.

Dose proportionality and the effect of food on vildagliptin, a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers.

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.

Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

OBJECTIVE: Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100 mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg oral dose of warfarin sodium. RESEARCH DESIGN AND METHODS: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects. RESULTS: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S-warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S-warfarin maximum plasma concentration (Cmax) were also within the equivalence range 0.80-1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PT(max), 1.00 [90% CI 0.97, 1.04]; AUC(PT), 0.99 [0.97, 1.01]) and international normalized ratios (INRmax, 1.01 [0.98, 1.05]; AUC(INR), 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80-1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication. CONCLUSIONS: Co-administration of warfarin with vildagliptin did not alter the pharmacokinetics and pharmacodynamics of R- or S-warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.