Mindy Magee

Potential for Pharmacokinetic Interactions Between Ambrisentan and Cyclosporine

Ambrisentan (ABS), approved for the treatment of pulmonary arterial hypertension and administered as an oral dose once daily, is an ETA‐selective endothelin receptor antagonist (ERA) and a potential substrate for cytochrome P450 (CYP) 3A4, organic anion–transporting polypeptide (OATP), and P‐glycoprotein (P‐gp). Cyclosporin A (CsA), an inhibitor of CYP3A4, P‐gp, and OATP, may be used concomitantly with ABS. In this open‐label, parallel‐treatment study, 28 healthy subjects received steady‐state ABS (5 mg q.d.) either alone or with steady‐state CsA (100–150 mg b.i.d.), and 24 other subjects received steady‐state CsA either alone or with steady‐state ABS. In the presence of CsA, ABS maximum plasma concentration (Cmax) increased 1.5‐fold, and area under the plasma concentration–time curve (AUC)0–τ increased twofold. Marginal increases were observed for CsA Cmax (906 vs. 1,014 ng/ml) and AUC0–τ (3.05 vs. 3.37 µg·h/ml) in the presence of ABS. Frequent adverse events (AEs) were headache and gastrointestinal disorders. The addition of ABS to steady‐state CsA appeared less tolerable as compared with the addition of CsA to steady‐state ABS. A maximum ABS dose of 5 mg is recommended if it is coadministered with CsA. No change in CsA dose is recommended if it is coadministered with ABS.

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.

Darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in diabetic macular edema: a 3-month placebo-controlled study.

PURPOSE To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME). DESIGN Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study. PARTICIPANTS Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18). METHODS Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months. MAIN OUTCOME MEASURES Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography. RESULTS Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 μm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 μm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups. CONCLUSIONS Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.

Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

Background We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials. Methods and Results Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0–10 µg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9–27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination. Conclusions Lp-PLA2 inhibition does not enhance platelet aggregation. Trial Registration 1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257

Disposition and Metabolism of Darapladib, a Lipoprotein-associated Phospholipase A2 Inhibitor, in Humans

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [14C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%–6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acid-catalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%–53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.

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.

Utility of concentration‐effect modeling and simulation in a thorough QT study of losmapimod

A thorough QT study was conducted in healthy volunteers with losmapimod. Four treatment regimens were included: a therapeutic dose (7.5 mg BID for 5 days), a supratherapeutic dose (20 mg QD for 5 days), a positive control (400 mg moxifloxacin single dose on Day 5), and placebo for 5 days. Baseline and on treatment ECGs were measured on Day 1 (3 timepoints predose) and Day 5, respectively. The primary statistical analysis failed to demonstrate a lack of effect of losmapimod on the QT interval leading to a positive finding. However, simulations using the concentration‐effect model established for QTcF vs. losmapimod concentration at concentrations 4× the maximum concentration of the therapeutic dose did not exceed the regulatory thresholds of concern of 5 milliseconds for the mean (4.57 milliseconds) and 10 milliseconds for the upper bound of the 90%CI (90%CI 2.88, 6.10). Modeling demonstrated that the discrepant results may have been due to a baseline shift after repeat dosing and baseline differences between the treatments. Considering the results of the concentration‐effect modeling, previous losmapimod data, and the high false‐positive rate associated with the ICH E14 statistical analysis, the statistical analysis was likely a false‐positive.

PkStaMp Library for Constructing Optimal Population Designs for PK/PD Studies

We discuss a Matlab-based library for constructing optimal sampling schemes for pharmacokinetic (PK) and pharmacodynamic (PD) studies. The software relies on optimal design theory for nonlinear mixed effects models and, in particular, on the first-order optimization algorithm. The library includes a number of popular compartmental PK and combined PK/PD models and can be extended to include more models. An outline of inputs/outputs is provided, some algorithmic details and examples are presented, and future work is discussed.

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib.

AIM/METHODS This was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12). RESULTS For total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration-time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml(-1)  h [90% CI 158, 316 ng ml(-1 ) h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml(-1 ) h [90% CI 159, 217 ng ml(-1 ) h], in healthy subjects) and maximum concentration (Cmax ) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (tmax ). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs. CONCLUSIONS The results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.