Rebecca E. Wrishko

Pharmacokinetic Interaction Between Tadalafil and Bosentan in Healthy Male Subjects

Tadalafil, an oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a treatment for pulmonary arterial hypertension. Bosentan is an oral endothelin receptor antagonist widely used in the treatment of pulmonary arterial hypertension. Tadalafil is mainly metabolized by cytochrome P450 (CYP) 3A4, and as bosentan induces CYP2C9 and CYP3A4, a pharmacokinetic interaction is possible between these agents. This open‐label, randomized study investigated whether any pharmacokinetic interaction exists between tadalafil and bosentan. Healthy adult men (n = 15; 19–52 years of age) received 10 consecutive days of tadalafil 40 mg once daily, bosentan 125 mg twice daily, and a combination of both in a 3‐period, crossover design. Following 10 days of multiple‐dose coadministration of bosentan and tadalafil, compared with tadalafil alone, tadalafil geometric mean ratios (90% confidence interval [CI]) for AUCτ and Cmax were 0.59 (0.55, 0.62) and 0.73 (0.68, 0.79), respectively, with no observed change in tmax. Following coadministration of bosentan with tadalafil, bosentan ratios (90% CI) for AUCτ and Cmax were 1.13 (1.02, 1.24) and 1.20 (1.05, 1.36), respectively. Tadalafil alone and combined with bosentan was generally well tolerated. In conclusion, after 10 days of coadministration, bosentan decreased tadalafil exposure by 41.5% with minimal and clinically irrelevant differences (<20%) in bosentan exposure.

Population Pharmacokinetic Analyses to Evaluate the Influence of Intrinsic and Extrinsic Factors on Exposure of Prasugrel Active Metabolite in TRITON‐TIMI 38

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON‐TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrels active metabolite (Pras‐AM) concentrations from its 2 downstream inactive metabolites. Population‐based methods were then applied to Pras‐AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras‐AM exposures was assessed. The PK of Pras‐AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras‐AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16–1.45) higher than exposure in patients ≥60 kg. Mean Pras‐AM exposures for patients ≥75 years (10.5%) were 19% (90% CI: 1.11–1.28) higher compared with patients <75 years.

Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end‐stage renal disease

Objective:  The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end‐stage renal impairment.

Safety, Efficacy, and Pharmacokinetic Overview of Low‐Dose Daily Administration of Tadalafil

INTRODUCTION Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. AIM To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. METHODS Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. MAIN OUTCOME MEASURES Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. RESULTS Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. CONCLUSIONS Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED.

CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD.

To determine whether physicians can adequately titrate atomoxetine without knowing genotype status for hepatic cytochrome P450 2D6, we pooled data from two open-label studies of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder. Patients were assessed weekly up to 10 weeks and doses titrated for efficacy and tolerability at the discretion of investigators (max. 1.8 mg/kg/d). Mean dose was 0.1 mg/kg/d lower in poor metabolizer (PM) patients (n=87) than extensive metabolizers (EMs, n=1239). PMs demonstrated marginally better efficacy on the ADHDRS-IV-Parent:Inv and had comparable safety profiles, except for a 4.0-bpm greater increase in mean pulse rate and a 1.0-kg greater weight loss. Changes from baseline in Fridericia QTc did not differ between groups or correlate with dose in PMs. Results suggest genotyping is unnecessary during routine clinical management, because investigators were able to dose atomoxetine to comparable efficacy and safety levels in EMs and PMs without knowledge of genotype metabolizer status.

Relationship Between Exposure to Prasugrel Active Metabolite and Clinical Outcomes in the TRITON-TIMI 38 Substudy

In TRITON‐TIMI 38, levels of the prasugrel active metabolite (pras‐AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras‐AM was observed in low‐weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non—coronary artery bypass graft (CABG)–related TIMI‐related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras‐AM and clinical outcomes was assessed in 1159 prasugrel‐treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras‐AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras‐AM exposure was associated with a higher incidence of non‐CABG‐related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non‐CABG‐related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras‐AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras‐AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.

Effect of age on the pharmacokinetics and pharmacodynamics of prasugrel during multiple dosing: an open-label, single-sequence, clinical trial.

BackgroundA substantial portion of patients at risk for acute coronary syndrome (ACS) are >65 years old. Prasugrel is a novel antiplatelet agent approved for the treatment of ACS patients undergoing percutaneous coronary intervention, and will be used in this population.ObjectiveThis study assessed the effect of age ≥65 years on the pharmacokinetics (PK) and pharmacodynamics (PD) of the active metabolite (R-138727) of prasugrel in healthy subjects taking aspirin (acetylsalicylic acid).MethodsThis was an open-label, single-sequence trial conducted in a single clinical research centre in the UK. A total of 17 subjects aged 65–80 years and 15 subjects aged 20–39 years received a prasugrel 5-mg once-daily maintenance dose for 10 days followed by 10-mg once daily maintenance doses for 10 days. All subjects also received aspirin 75 mg daily. Serial blood samples were collected pre-dose and at various times post-dose for measurement of the active metabolite of prasugrel in plasma on days 10 and 20, following the last 5- and 10-mg prasugrel dose, respectively. PK parameters of the active metabolite of prasugrel included area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast), maximum plasma concentration (Cmax) and time to Cmax (tmax). Maximal platelet aggregation (MPA), assessed by light transmission aggregometry using adenosine diphosphate (ADP) 20 µmol/L, was assessed at baseline and on day 10 (5-mg maintenance dose) and day 20 (10-mg maintenance dose). Bleeding times (BTs) were determined on days −5, 1, 10, 11, 20 and 21 using a modified Ivy technique.ResultsAUClast did not differ significantly between age groups. The steady-state trough MPA to ADP 20 µmol/L during 10-mg maintenance dosing was 30.6% and 26.6% in elderly and young subjects, respectively. Mean MPA was consistently higher in elderly subjects compared with young subjects; however, differences were generally less than ten percentage points. BTs did not differ between the two populations during 5-mg maintenance dosing; however, during 10-mg maintenance dosing, BTs were up to 67% longer in young compared with elderly subjects. A higher frequency of minor bleeding during 10-mg maintenance dosing was observed in elderly subjects compared with young subjects.ConclusionsThese data indicate that prasugrel PK and MPA were similar in healthy subjects regardless of age. Compared with younger subjects, elderly subjects had shorter BTs but a greater frequency of mild bleeding-related adverse events.

Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis.

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras‐AM), which inhibits adenosine diphosphate (ADP)–induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras‐AM from downstream inactive metabolites, R‐119251 and R‐106583, for the purpose of estimating Pras‐AM exposure in patients in the TRITON‐TIMI 38 sub‐studies. The model development included 1462 Pras‐AM, 1345 R‐119251, and 1456 R‐106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg. The model was shown to provide good correlation between predicted and observed concentrations with only a minor deviation of ∼6% from the unity line and described the variability within ∼4.5%. Examination of the data indicated that regardless of ethnicity, age, weight, moderate hepatic impairment, or renal impairment, predictions were reliable. Predicted Pras‐AM concentrations in TRITON‐TIMI 38 were comparable with historical data.