Arun Mandagere

No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers

Ambrisentan is a nonsulfonamide, ET(A)-selective endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), and tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor under investigation for treatment of PAH. Due to the potential combination use, the pharmacokinetic (PK) interactions between these two drugs were assessed in a crossover study in 26 healthy adults. Single-dose PK of ambrisentan (10 mg) and its metabolite, 4-hydroxymethyl ambrisentan, were determined in the absence and presence of multiple doses of tadalafil (40 mg QD). Similarly, single-dose PK of tadalafil (40 mg) were evaluated in the absence and presence of multiple doses of ambrisentan (10 mg QD). In the presence of tadalafil, ambrisentan maximum plasma concentration (C(max)) was similar (105.0% [90% CI: 95.9-115.0%]) and systemic exposure (AUC(0-infinity)) was slightly decreased (87.5% [84.0-91.2%]), compared with ambrisentan alone. Similar changes were observed with 4-hydroxymethyl ambrisentan. Tadalafil C(max) (100.6% [94.4-107.1%]) and AUC(0-infinity) (100.2% [92.6-108.4%]) showed no difference in the absence and presence of ambrisentan. The safety profile of the drugs combined was similar to that of either drug alone. No dose adjustments should be necessary when these drugs are coadministered. These results are in contrast to previous reports that the sulfonamide-based ERA bosentan can cause marked decreases in the exposure of tadalafil.

Pharmacokinetics and Safety of Ambrisentan in Combination With Sildenafil in Healthy Volunteers

The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE‐5) inhibitor, and ambrisentan, an ETA‐selective, propanoic acid—based endothelin receptor antagonist (ERA), was studied in a 2‐period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC0‐∞) and maximum plasma concentration (Cmax) determined over 24 hours for a 10‐mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC0‐∞ and Cmax for sildenafil and N‐desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20‐mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N‐desmethyl sildenafil. Ambrisentan Cmax was unchanged (96.3% [90% confidence interval: 86.0%‐107.8%]), with a minor increase in AUC0‐∞(108.5% [102.6%‐111.7%]) with sildenafil coadministration. Sildenafil Cmax was increased slightly (113.4% [99.6%‐129.1%]), and AUC0‐∞ was unchanged (98.7% [91.2%‐110.5%]) with ambrisentan coadministration. N‐desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.

The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

AIMS Ambrisentan is an oral, propanoic acid-based endothelin receptor antagonist often co-administered with warfarin to patients with pulmonary arterial hypertension. The aim of this study was to evaluate the potential for ambrisentan to affect warfarin pharmacokinetics and pharmacodynamics. METHODS In this open-label cross-over study, 22 healthy subjects received a single dose of racemic warfarin 25 mg alone and after 8 days of ambrisentan 10 mg once daily. Assessments included exposure (AUC(0-last)) and maximum plasma concentration (C(max)) for R- and S-warfarin, and International Normalized Ratio maximum observed value (INR(max)) and area under the curve (INR(AUC(0-last))). The effects of warfarin on ambrisentan steady-state pharmacokinetics and the safety of ambrisentan/warfarin co-administration were assessed. Data are presented as geometric mean ratios. RESULTS Ambrisentan had no significant effects on the AUC(0-last) of R-warfarin [104.7; 90% confidence interval (CI) 101.7, 107.7) or S-warfarin (101.6; 90% CI 98.4, 105.0). Similarly, ambrisentan had no significant effects on the C(max) of R-warfarin (91.6; 90% CI 86.2, 97.4) or S-warfarin (89.9; 90% CI 84.8, 95.3). Consistent with these observations, little pharmacodynamic change was observed for INR(max) (85.3; 90% CI 82.4, 88.2) or INR(AUC(0-last)) (93.0; 90% CI 90.8, 95.3). In addition, co-administration of warfarin did not alter ambrisentan steady-state pharmacokinetics. Adverse events were infrequent, and there were no bleeding adverse events. CONCLUSIONS Multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics and pharmacodynamics of a single dose of warfarin. Therefore, significant dose adjustments of either drug are unlikely to be required with co-administration.

Effect of ketoconazole on the pharmacokinetic profile of ambrisentan.

Ambrisentan is an endothelin type A (ETA)–selective receptor antagonist that is metabolized primarily by glucuronidation but also undergoes oxidative metabolism by CYP3A4. The potential for ketoconazole, the archetypal strong inhibitor of CYP3A4, to alter the pharmacokinetic profile of ambrisentan and its oxidative metabolite, 4‐hydroxymethyl ambrisentan, was assessed in an open‐label, nonrandomized, 2‐period, single‐sequence study in 16 healthy men. Participants received a single dose of ambrisentan 10 mg alone and after 4 days of ketoconazole 400 mg administered once daily. In the presence of multiple doses of ketoconazole, single‐dose ambrisentan AUC0–∞ estimate was increased by 35.3%, whereas Cmax was increased by 20.0%. For the 4‐hydroxymethyl ambrisentan metabolite, AUC0–∞ estimate was decreased by 4.0%, whereas Cmax was decreased by 16.5%. Concomitant administration of ambrisentan and ketoconazole was well tolerated. In summary, ketoconazole had no clinically significant effect on the pharmacokinetics or safety profile of ambrisentan; therefore, no changes in ambrisentan dose should be necessary when the drug is administered concomitantly with known CYP3A4 inhibitors.

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.

Effects of multiple doses of ambrisentan on the pharmacokinetics of a single dose of digoxin in healthy volunteers.

J Clin Phar acol 2011;51:102-106 A is a high-affinity, propanoic acid– based, endothelin type A (ETA)–selective endothelin receptor antagonist. In phase 3 studies, ambrisentan improved exercise capacity, delayed clinical worsening, and improved symptoms of pulmonary arterial hypertension (PAH). Ambrisentan is metabolized primarily by glucuronidation via several uridine glucuronosyltransferase enzymes. Ambrisentan undergoes oxidative metabolism by cytochrome (CYP) 3A4 and to a lesser extent by CYP3A5 and CYP2C19. Clinical pharmacology studies with several drugs that may be given in PAH (sildenafil, warfarin, and ketoconazole) show that ambrisentan may be given concomitantly without dose adjustment. In vitro investigations in Caco-2 cells indicate that ambrisentan is a substrate for P-glycoprotein (P-gp). Ambrisentan did not inhibit human P-gp– mediated transport of digoxin in Madin-Darby canine kidney cells at concentrations up to 100 μM and did not induce P-gp expression in rats administered 100 μM ambrisentan for 4 days. Digoxin is indicated for the treatment of heart failure and chronic atrial fibrillation but is also generally believed to have beneficial effects as a supportive treatment in PAH. Digoxin was a concomitant medication in 11% of patients in ambrisentan phase 3 clinical studies. Excretion of digoxin is largely dependent on the action of P-gp and is therefore affected by drugs that inhibit or induce P-gp. Furthermore, endothelin receptor antagonists have the potential to alter renal blood flow. Changes in blood flow have been associated with changes in the elimination of digoxin. Therefore, the effects of multiple doses of ambrisentan on the pharmacokinetics of a single dose of digoxin were evaluated in this study.