Ramesh Boinpally

Effects of rifampicin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study.

AbstractBackground: Ambrisentan is a once-daily, endothelin (ET) type A receptor-selective antagonist approved for the treatment of pulmonary arterial hypertension. Ambrisentan is primarily metabolized by glucuronidation and undergoes cytochrome P450 (CYP)-mediated oxidation to a lesser extent. Objective: To assess the effects of rifampicin (rifampin), a potent inducer of CYP3A4 and inhibitor of organic anion transporter polypeptides (OATPs), on the steady-state pharmacokinetics, safety and tolerability of ambrisentan. Methods: This was a 14-day, single-sequence, open-label study that was conducted in 24 healthy adults. Subjects were administered oral doses of ambrisentan (10 mg) once daily on days 1 through 5 and were then co-administered ambrisentan (10 mg) plus rifampicin (600 mg) once daily on days 6 through 13. The steady-state pharmacokinetics of ambrisentan and its oxidative metabolite 4-hydroxymethyl ambrisentan were determined in the absence and presence of repeated administration of rifampicin. The main outcome measure was the analysis of ambrisentan pharmacokinetics (area under the plasma concentration-time curve during a dosage interval [AUCτ], maximum plasma drug concentration [Cmax] and minimum plasma drug concentration [Cmin]) for steady-state ambrisentan alone (day 5) as compared with steady-state ambrisentan plus steady-state rifampicin (day 13). Adverse events (AEs), ECG recordings, vital signs and clinical laboratory parameters were monitored throughout the study and at follow-up. Results: A transient increase (+87% [95% CI 79, 95]) in ambrisentan steadystate systemic exposure (AUCτ) was observed during the first 2 days of rifampicin co-administration. However, in the presence of steady-state rifampicin, ambrisentan Cmax and AUCτ values were similar (+2% [95% CI −7, 12] and −4% [−9, 2], respectively) to those observed for ambrisentan alone. Relative systemic exposure of 4-hydroxymethyl ambrisentan was unaffected by either acute or steady-state rifampicin. No serious AEs or AEs leading to withdrawal were reported and there were no clinically significant changes in vital signs, ECG recordings or clinical laboratory parameters with co-administration of ambrisentan and rifampicin. Conclusion: Steady-state rifampicin had no clinically relevant effects on the steady-state pharmacokinetics of ambrisentan. The overall safety profile of ambrisentan was similar in the presence and absence of rifampicin. No dose adjustment of ambrisentan should be required when it is co-administered with rifampicin, a strong inducer of CYP3A4 activity and inhibitor of OATPs.

Effect of Steady-State Ambrisentan on the Pharmacokinetics of a Single Dose of the Oral Contraceptive Norethindrone (Norethisterone) 1 mg/Ethinylestradiol 35 μg in Healthy Subjects

AbstractBackground: Ambrisentan is an oral, once-daily endothelin receptor antagonist (ERA) that is approved for the treatment of pulmonary arterial hypertension (PAH). Pregnancy is not recommended for women of childbearing potential with PAH, due to an increased risk of mortality. Additionally, the ERA class is teratogenic in animal studies. A highly effective method of contraception is therefore strongly recommended for women of childbearing potential who are treated with an ERA for PAH. Objective: This study investigated the effect of ambrisentan on the pharmacokinetics (PK) of the oral contraceptive norethindrone (norethisterone) 1 mg/ethinylestradiol 35 μg (NT 1 mg/EE 35 μg ). Methods: The study was an open-label, single-sequence, PK study designed to assess the effect of multiple doses of ambrisentan (Letairis®; Volibris®) on the PK of a single oral dose of NT 1 mg/EE 35 μg (Ortho-Novum® 1/35) in a single clinical research centre in the US. The study included 28 healthy female subjects in general good health, aged 18–45 years, and who had a body mass index of 18.5–29.9 kg/m2. A single oral dose of NT 1 mg/EE 35 μg was administered on day 1. On day 10, following a wash-out period, fasted subjects received once-daily 10 mg doses of ambrisentan for 12 days. On day 22, a single oral dose of NT 1 mg/EE 35 μg and a single 10 mg oral dose of ambrisentan were coadministered; thereafter, subjects continued to receive once-daily oral doses of ambrisentan 10 mg on days 23 through 26. The primary PK endpoints included maximum observed plasma drug concentration (Cmax), time to reach Cmax (tmax), and the area under the plasma concentration-time curve from time zero to the time of last measurable concentration (AUClast). Results: Ethinylestradiol Cmax was slightly decreased (geometric mean ratio [GMR] 91.7%; 90% CI 86.1,97.8) and AUClast was similar (GMR 99.1%; 90% CI 91.0, 107.9) in the presence of ambrisentan compared with NT 1 mg/EE 35 μg. Norethindrone Cmax (GMR 113.2%; 90% CI 102.4, 125.1) and AUC[inlast] (GMR 112.9%; 90% CI 104.9,121.6) were slightly increased in the presence of ambrisentan. The 90% CIs were within the pre-defined no-effect boundaries for all PK parameters, except for the Cmax of norethindrone, which was slightly above the upper limit of 125%. No safety concerns were apparent with the coadministration of NT 1 mg/EE 35 μg and ambrisentan. Conclusion: No dose adjustment of the oral contraceptive NT 1 mg/EE 35 μg is warranted with the coadministration of ambrisentan.

Influence of CYP3A4 Induction/Inhibition on the Pharmacokinetics of Vilazodone in Healthy Subjects

PURPOSE Vilazodone is a serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP-mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone. METHODS Participants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and Cmax for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and Cmax were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded. FINDINGS In study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated. IMPLICATIONS These results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.).

Correlation between the systemic clearance of drugs and their food effects in humans

Context: Food effects were defined as positive, when coadministration of food causes an increase in the extent of absorption (AUC0–∞) of a drug when compared with fasted state drug administration and no effect when coadministration of food causes no change in AUC0–∞. In general, low solubility drugs exhibit positive food effects due to improved solubility in fed state administration. But, certain high-solubility and high-permeability drugs that undergo extensive presystemic metabolism exhibit positive food effects because of the increased splanchnic hepatic blood flow in the fed state presumably causing a fraction of drug to bypass first-pass metabolism during absorption. Objective: In this study, systemic clearance (Cl) of structurally diverse high-permeability and high-solubility drugs was correlated to their food effects to explore whether drugs undergoing low clearance exhibited no food effects and drugs undergoing high clearance exhibited positive food effects. Methods: Six drugs exhibiting positive food effects and nine drugs exhibiting no food effects (for comparison) were selected for linear regression analysis. Results: Regression analysis of the selected drugs indicated that percent food effects correlated linearly to Cl and fitted the equation: percent food effects = 0.9163 × Cl − 6.4789. The R2, p-value and power of the regression model were >0.88, 0.9999, respectively indicating the direct correlation between Cl and food effects of the selected model drugs; other statistical tests validated the model. Conclusion: The model indicated that high-solubility and high-permeability drugs undergoing Cl of more than 27 L/h may exhibit statistically significant positive food effects.

Pharmacokinetics and Safety of Vilazodone in Hepatic Impairment.

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder, is extensively hepatically metabolized. The pharmacokinetics, tolerability, and safety of vilazodone were investigated in 2 trials comparing participants with hepatic impairment with healthy controls. In these phase 1, open-label, parallel-group, single-dose pharmacokinetic studies, vilazodone (20 mg) was administered to participants with mild, moderate, or severe hepatic impairment or individually matched healthy controls. Vilazodone and M17 (the major metabolite) concentrations in plasma were analyzed using validated liquid chromatography with tandem mass spectrometry. Forty-eight participants (8 each in mild, moderate, and severe hepatic impairment groups with matched healthy controls) were evaluated for pharmacokinetic analyses. All pharmacokinetic parameters in participants with mild and moderate hepatic impairment were similar to those in healthy controls. Mean Cmax and AUC0–∞ were approximately 29% and 17% lower in participants with severe hepatic impairment compared with healthy participants; values for Tmax, and t1/2 were similar between groups. Diarrhea was experienced by more participants with hepatic impairment than controls (10 vs. 5, respectively), and vomiting (4 participants) occurred only in participants with severe hepatic impairment; other adverse events were roughly equivalent between groups. Following a single, 20-mg oral dose of vilazodone, pharmacokinetics were similar in participants with mild, moderate, or severe hepatic impairment and healthy controls. No dose adjustment is needed for patients with major depressive disorder who have mild, moderate, or severe hepatic impairment.