RESUMO
The pharmacokinetics, metabolism, and excretion of cobimetinib, a MEK inhibitor, were characterized in healthy male subjects (n = 6) following a single 20 mg (200 µCi) oral dose. Unchanged cobimetinib and M16 (glycine conjugate of hydrolyzed cobimetinib) were the major circulating species, accounting for 20.5% and 18.3% of the drug-related material in plasma up to 48 hours postdose, respectively. Other circulating metabolites were minor, accounting for less than 10% of drug-related material in plasma. The total recovery of the administered radioactivity was 94.3% (±1.6%, S.D.) with 76.5% (±2.3%) in feces and 17.8% (±2.5%) in urine. Metabolite profiling indicated that cobimetinib had been extensively metabolized with only 1.6% and 6.6% of the dose remaining as unchanged drug in urine and feces, respectively. In vitro phenotyping experiments indicated that CYP3A4 was predominantly responsible for metabolizing cobimetinib. From this study, we concluded that cobimetinib had been well absorbed (fraction absorbed, Fa = 0.88). Given this good absorption and the previously determined low hepatic clearance, the systemic exposures were lower than expected (bioavailability, F = 0.28). We hypothesized that intestinal metabolism had strongly attenuated the oral bioavailability of cobimetinib. Supporting this hypothesis, the fraction escaping gut wall elimination (Fg) was estimated to be 0.37 based on F and Fa from this study and the fraction escaping hepatic elimination (Fh) from the absolute bioavailability study (F = Fa × Fh × Fg). Physiologically based pharmacokinetics modeling also showed that intestinal clearance had to be included to adequately describe the oral profile. These collective data suggested that cobimetinib was well absorbed following oral administration and extensively metabolized with intestinal first-pass metabolism contributing to its disposition.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Azetidinas/administração & dosagem , Azetidinas/farmacocinética , Absorção Intestinal , Mucosa Intestinal/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Eliminação Renal , Administração Oral , Adulto , Antineoplásicos/sangue , Antineoplásicos/urina , Azetidinas/sangue , Azetidinas/urina , Disponibilidade Biológica , Biotransformação , Radioisótopos de Carbono , Citocromo P-450 CYP3A/metabolismo , Fezes/química , Glicina/metabolismo , Voluntários Saudáveis , Humanos , Hidrólise , Intestinos/enzimologia , Masculino , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Piperidinas/sangue , Piperidinas/urina , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/urina , Especificidade por Substrato , Adulto JovemRESUMO
Cobimetinib is a potent and highly selective inhibitor of MEK1/2. Since cobimetinib exhibited absorption variability in cancer patients, a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation, food, and elevated gastric pH on cobimetinib bioavailability. Three crossover trials were performed with a 20 mg cobimetinib oral dose: absolute bioavailability using a 2 mg intravenous infusion (n = 13), relative bioavailability of tablets versus capsules and food effect (n = 20), and drug interaction with a proton pump inhibitor (20 mg of rabeprazole daily for 5 days prior to cobimetinib administration; n = 20). Absolute bioavailability of cobimetinib was 46.2% (24.2, CV %), likely due to metabolism rather than incomplete absorption. The mean systemic clearance of cobimetinib was low (11.7 L/h [28.2, CV %]). Administration of cobimetinib tablets with a high-fat meal delayed drug absorption (prolonged tmax) but had no statistically significant effect on cobimetinib exposure (Cmax and AUC0-∞). Tablet and capsule formulations of cobimetinib showed comparable exposures. Cobimetinib exhibited delayed absorption (tmax) in the presence of rabeprazole, with no statistically significant effects on drug exposure (Cmax and AUC0-∞) in the fasted state. In conclusion, cobimetinib oral absorption was not affected by change in formulation, food, or elevated gastric pH.
Assuntos
Azetidinas/farmacocinética , Alimentos , Piperidinas/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol/farmacologia , Absorção/efeitos dos fármacos , Administração Oral , Adulto , Disponibilidade Biológica , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Adulto JovemRESUMO
Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.
Assuntos
Acloridria/induzido quimicamente , Acloridria/tratamento farmacológico , Betaína/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , Rabeprazol/efeitos adversos , Adulto , Antiulcerosos/efeitos adversos , Feminino , Voluntários Saudáveis , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-IdadeRESUMO
Acid-reducing agents (ARAs) are the most commonly prescribed medications in North America and Western Europe. There are currently no data describing the prevalence of their use among cancer patients. However, this is a paramount question due to the potential for significant drug-drug interactions (DDIs) between ARAs, most commonly proton pump inhibitors (PPIs), and orally administered cancer therapeutics that display pH-dependent solubility, which may lead to decreased drug absorption and decreased therapeutic benefit. Of recently approved orally administered cancer therapeutics, >50% are characterized as having pH-dependent solubility, but there are currently no data describing the potential for this ARA-DDI liability among targeted agents currently in clinical development. The objectives of this study were to (1) determine the prevalence of ARA use among different cancer populations and (2) investigate the prevalence of orally administered cancer therapeutics currently in development that may be liable for an ARA-DDI. To address the question of ARA use among cancer patients, a retrospective cross-sectional analysis was performed using two large healthcare databases: Thomson Reuters MarketScan (N = 1,776,443) and the U.S. Department of Veterans Affairs (VA, N = 1,171,833). Among all cancer patients, the total prevalence proportion of ARA use (no. of cancer patients receiving an ARA/total no. of cancer patients) was 20% and 33% for the MarketScan and VA databases, respectively. PPIs were the most commonly prescribed agent, comprising 79% and 65% of all cancer patients receiving a prescription for an ARA (no. of cancer patients receiving a PPI /no. of cancer patients receiving an ARA) for the MarketScan and VA databases, respectively. To estimate the ARA-DDI liability of orally administered molecular targeted cancer therapeutics currently in development, two publicly available databases, (1) Kinase SARfari and (2) canSAR, were examined. For those orally administered clinical candidates that had available structures, the pKa's and corresponding relative solubilities were calculated for a normal fasting pH of 1.2 and an "ARA-hypochlorhydric" pH of 4. Taking calculated pKa's and relative solubilities into consideration, clinical candidates were classified based on their risk for an ARA-DDI. More than one-quarter (28%) of the molecules investigated are at high risk for an ARA-DDI, and of those high risk molecules, nearly three-quarters (73%) are being clinically evaluated for at least one of five cancer types with the highest prevalence of ARA use (gastrointestinal, pancreatic, lung, glioblastoma multiforme, gastrointestinal stromal tumor (GIST)). These data strongly suggest that with the clinical development of ARA-DDI-susceptible cancer therapeutics will come continued challenges for drug-development scientists, oncologists, and regulatory agencies in ensuring that patients achieve safe and efficacious exposures of their cancer therapeutics and thus optimal patient outcomes.
Assuntos
Interações Medicamentosas , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores da Bomba de Prótons/farmacocinética , Estudos Retrospectivos , Estados UnidosRESUMO
GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median Tmax of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median Tmax of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0-∞ and 0.87 (0.70, 1.06) for Cmax. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median Tmax was unchanged, however, both Cmax and AUC0-∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0-∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the Cmax (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.
Assuntos
Antineoplásicos/farmacocinética , Indazóis/farmacocinética , Inibidores da Bomba de Prótons/efeitos adversos , Rabeprazol/efeitos adversos , Sulfonamidas/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Interações Alimento-Droga , Voluntários Saudáveis , Concentração de Íons de Hidrogênio , SolubilidadeRESUMO
INTRODUCTION: Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval. METHODS AND RESULTS: Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed. This dedicated QTc study was powered to exclude a 20-millisecond change from the baseline QTc interval. The subjects were administered daily oral 150 mg of vismodegib for 7 days, or a single dose of 400 mg of moxifloxacin, with corresponding matching placebos. The upper limits of the 90% confidence intervals for the difference in ΔQTcF between vismodegib and placebo at steady state were <20 milliseconds at all timepoints with a maximum of 10 milliseconds at 12 hours postdose. Exposure-response analysis yielded an estimated slope equal to 0.11 ms/µM, which was not statistically significant. After a single dose of moxifloxacin was administered, the lower limits of the 90% confidence interval of the difference in ΔQTcF between moxifloxacin and placebo were >5 milliseconds from 1-12 hours postdose, thereby establishing assay sensitivity. CONCLUSIONS: There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state.
Assuntos
Anilidas/administração & dosagem , Antineoplásicos/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Idoso , Anilidas/efeitos adversos , Anilidas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Compostos Aza/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Eletrocardiografia , Feminino , Fluoroquinolonas , França , Frequência Cardíaca/efeitos dos fármacos , Humanos , Modelos Lineares , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Pessoa de Meia-Idade , Modelos Biológicos , Moxifloxacina , Piridinas/efeitos adversos , Piridinas/farmacocinética , Quinolinas/administração & dosagem , Medição de Risco , Fatores de TempoRESUMO
Potential differences in pharmacokinetics (PK) between healthy subjects and patients with cancer were investigated using a physiologically based pharmacokinetic approach integrating demographic and physiological data from patients with cancer. Demographic data such as age, sex and body weight, and clinical laboratory measurements such as albumin, alpha-1 acid glycoprotein (AAG) and hematocrit were collected in ~2500 patients with cancer. A custom oncology population profile was built using the observed relationships among demographic variables and laboratory measurements in Simcyp® software, a population based ADME simulator. Patients with cancer were older compared with the age distribution in a built-in healthy volunteer profile in Simcyp. Hematocrit and albumin levels were lower and AAG levels were higher in patients with cancer. The custom population profile was used to investigate the disease effect on the pharmacokinetics of two probe substrates, saquinavir and midazolam. Higher saquinavir exposure was predicted in patients relative to healthy subjects, which was explained by the altered drug binding due to elevated AAG levels in patients with cancer. Consistent with historical clinical data, similar midazolam exposure was predicted in patients and healthy subjects, supporting the hypothesis that the CYP3A activity is not altered in patients with cancer. These results suggest that the custom oncology population profile is a promising tool for the prediction of PK in patients with cancer. Further evaluation and extension of this population profile with more compounds and more data will be needed.
Assuntos
Midazolam/farmacocinética , Modelos Biológicos , Neoplasias/metabolismo , Saquinavir/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiolíticos/farmacocinética , Índice de Massa Corporal , Tamanho Corporal , Peso Corporal , Feminino , Inibidores da Protease de HIV/farmacocinética , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Orosomucoide/análise , Albumina Sérica/análise , Adulto JovemRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS: This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIM: Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. METHODS: Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. RESULTS: Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION: Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.
Assuntos
Anilidas/farmacocinética , Antineoplásicos/farmacocinética , Piridinas/farmacocinética , Anilidas/administração & dosagem , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Injeções Intravenosas , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Dinâmica não Linear , Ligação Proteica , Piridinas/administração & dosagem , Solubilidade , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.
Assuntos
Benzilaminas/farmacocinética , Ejaculação/efeitos dos fármacos , Naftalenos/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Benzilaminas/administração & dosagem , Benzilaminas/sangue , Benzilaminas/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/sangue , Naftalenos/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/metabolismoRESUMO
Dapoxetine is being developed as a treatment for premature ejaculation and has demonstrated rapid absorption and elimination in previous pharmacokinetic studies. Two open-label studies were conducted in healthy men: a parallel-group pharmacokinetic and safety study in young and elderly men and a randomized crossover food-effect study. Maximal plasma dapoxetine concentrations (C(max)) were similar in young and elderly men (338 and 310 ng/mL, respectively), as were the corresponding area under the plasma concentration versus time curve (AUC) values (2040 and 2280 ng x h/mL, respectively). When coadministered with food, C(max) was reduced by 11% (398 vs 443 ng/mL in the fed and fasted states, respectively), and the peak was delayed by approximately 30 minutes, indicating that food slowed the rate of absorption; however, systemic exposure to dapoxetine (ie, AUC) was not affected by food consumption. Thus, age or consumption of a high-fat meal has only a modest impact on dapoxetine pharmacokinetics in healthy men.
Assuntos
Envelhecimento/fisiologia , Benzilaminas/farmacocinética , Benzilaminas/uso terapêutico , Gorduras na Dieta/farmacologia , Ejaculação/efeitos dos fármacos , Naftalenos/farmacocinética , Naftalenos/uso terapêutico , Adolescente , Adulto , Idoso , Benzilaminas/sangue , Estudos Cross-Over , Alimentos , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/sangueRESUMO
Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences.
Assuntos
Antifúngicos/farmacocinética , Itraconazol/farmacocinética , Cetoconazol/farmacocinética , Antifúngicos/administração & dosagem , Ensaios Clínicos como Assunto , Interações Medicamentosas , Humanos , Itraconazol/administração & dosagem , Cetoconazol/administração & dosagemRESUMO
PURPOSE: The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics. METHODS: Cohorts included a control arm (n = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n = 24); itraconazole 200 mg (n = 22); or fluconazole 400 mg (n = 22). RESULTS: Area under the vismodegib concentration-time curve from zero to 24 h (AUC0-24h) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC0-24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib. CONCLUSION: The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug-drug interaction. CLINICALTRIALS. GOV IDENTIFIER: NCT01772290.
Assuntos
Anilidas/farmacocinética , Fluconazol/farmacologia , Itraconazol/farmacologia , Piridinas/farmacocinética , Rabeprazol/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anilidas/administração & dosagem , Área Sob a Curva , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Feminino , Fluconazol/administração & dosagem , Humanos , Concentração de Íons de Hidrogênio , Itraconazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Piridinas/administração & dosagem , Rabeprazol/administração & dosagem , SolubilidadeRESUMO
Many orally administered, small-molecule, targeted anticancer drugs, such as dasatinib, exhibit pH-dependent solubility and reduced drug exposure when given with acid-reducing agents. We previously demonstrated that betaine hydrochloride (BHCl) can transiently re-acidify gastric pH in healthy volunteers with drug-induced hypochlorhydria. In this randomized, single-dose, three-way crossover study, healthy volunteers received dasatinib (100 mg) alone, after pretreatment with rabeprazole, and with 1500 mg BHCl after rabeprazole pretreatment, to determine if BHCl can enhance dasatinib absorption in hypochlorhydric conditions. Rabeprazole (20 mg b.i.d.) significantly reduced dasatinib Cmax and AUC0-∞ by 92 and 78%, respectively. However, coadministration of BHCl significantly increased dasatinib Cmax and AUC0-∞ by 15- and 6.7-fold, restoring them to 105 and 121%, respectively, of the control (dasatinib alone). Therefore, BHCl reversed the impact of hypochlorhydria on dasatinib drug exposure and may be an effective strategy to mitigate potential drug-drug interactions for drugs that exhibit pH-dependent solubility and are administered orally under hypochlorhydric conditions.
Assuntos
Absorção Fisiológica/efeitos dos fármacos , Acloridria/metabolismo , Antineoplásicos/farmacocinética , Betaína/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Pirimidinas/farmacocinética , Rabeprazol/farmacologia , Tiazóis/farmacocinética , Acloridria/induzido quimicamente , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Área Sob a Curva , Betaína/administração & dosagem , Estudos Cross-Over , Dasatinibe , Interações Medicamentosas , Feminino , Ácido Gástrico/química , Voluntários Saudáveis , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/sangue , Inibidores da Bomba de Prótons/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Rabeprazol/sangue , Rabeprazol/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/sangue , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach. METHODS: In this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (θ(BW_CL)) and on the central volume of distribution (θ(BW_V1)). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [C(min)] and peak serum concentration [C(max)]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study. RESULTS: Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of θ(BW_CL) and θ(BW_V1) in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight-based dosing; when both θ(BW_CL) and θ(BW_V1) are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θ(BW_CL) or θ(BW_V1) is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (θ(BW_CL) and θ(BW_V1) <0.5 or â¼0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%. CONCLUSIONS: The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Modelos Biológicos , Adulto , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Superfície Corporal , Peso Corporal , Simulação por Computador , Bases de Dados Factuais , Árvores de Decisões , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Taxa de Depuração MetabólicaRESUMO
To understand the roles that nucleoside transporters play in the in vivo distribution of clinically important nucleoside analogs, the substrate specificity of each transporter isoform should be determined. In the present work, we studied the substrate specificities of the human and rat orthologs of the Na+-dependent purine-selective nucleoside transporter (SPNT; concentrative nucleoside transporter 2), for nucleosides, nucleobases, and base- and ribose-modified nucleoside analogs. The two-electrode voltage-clamp technique in Xenopus laevis oocytes expressing these transporters was used. Purine nucleosides and uridine induced currents in oocytes expressing rat SPNT (rSPNT) or human SPNT1 (hSPNT1). The rank order of magnitude of nucleoside-induced currents was guanosine > uridine > adenosine > inosine and guanosine > uridine > inosine > adenosine for rSPNT- and hSPNT1-expressing oocytes, respectively. Uridine analogs (modified at the 5-position of the base) induced little or no current, suggesting that these compounds are only poorly transported by either transporter. Cladribine induced currents in oocytes expressing rSPNT (K(0.5) = 57 +/- 12 microM) but not hSPNT1. The ribose-modified nucleoside analogs, adenine arabinoside, and 2',3'-dideoxyadenosine induced currents in rSPNT-expressing, but not in hSPNT1-expressing, oocytes. These data suggest that there are notable species differences in the specificity of SPNT for synthetic nucleoside analogs.
Assuntos
Proteínas de Membrana Transportadoras/fisiologia , Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Guanosina/metabolismo , Humanos , Técnicas In Vitro , Potenciais da Membrana/fisiologia , Proteínas de Membrana Transportadoras/química , Dados de Sequência Molecular , Oócitos/fisiologia , Técnicas de Patch-Clamp , Ratos , Sódio/metabolismo , Especificidade da Espécie , Xenopus laevisRESUMO
UNLABELLED: We studied the inhibition of fetal (gamma-nAChR) and adult (epsilon-nAChR) muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium, vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary RNAs. Functional channels were activated with 10 microM acetylcholine, alone or in combination with various concentrations of the NDMRs. Currents were recorded with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion. Potencies of rapacuronium and Org 9488 were not statistically different at either gamma-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or epsilon-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank order of potencies at the epsilon-nAChR (pancuronium > vecuronium similar mivacurium > rocuronium similar d-tubocurarine > rapacuronium similar Org 9488 > gallamine) correlated highly with the clinical doses needed to produce 50% twitch depression at the adductor pollicis muscle in adults. Neuromuscular blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different drug-receptor affinities of the tested NDMRs contribute to the differences in clinical dose requirements of these drugs needed to achieve appropriate muscle relaxation. IMPLICATIONS: Potencies of nondepolarizing muscle relaxants, studied at muscle nicotinic acetylcholine receptors expressed in a recombinant expression system, correlate highly with the clinical doses needed in adults to produce 50% twitch depression at the adductor pollicis muscle.