Primary Objective: To characterize the pharmacokinetics (PK) of tadalafil in a pediatric population with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further clinical research.
Secondary Objective: To assess the tolerability and safety of tadalafil in a pediatric population with PAH; To compare tadalafil PK profile in a pediatric population with historical adult data from StudyH6D-MC-LVGY; To determine appropriate dose ranges for use in the evaluation of efficacy and safety of tadalafil; To clinically assess the palatability of the tadalafil suspension.
Pulmonary arterial hypertension (PAH) is a rare, chronic, and progressive disease characterized by elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right heart failure and death (Rich 1998; Barst 2004). Pulmonary arterial hypertension can be further classified into idiopathic PAH (IPAH), heritable PAH (FPAH), and associated PAH (APAH). Conditions that are associated with PAH include connective tissue diseases, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV) infection, schistosomiasis and some drugs (particularly anorexigens). The pathogenesis, presentation, diagnosis and management of PAH in children is similar to that in adults, though little research has been conducted in the pediatric population. The prevalence and incidence of PAH is significantly lower in children than in adults (Rubin 1997); it has been estimated that about 0.5 per million children will be diagnosed with IPAH which accounts for about 50% of all pediatric PAH. The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL Registry), a multicenter, observational, US-based registry created to provide the characteristics and treatment patterns of patients with PAH, recently reported just 184 prevalent pediatric cases among 54 enrolling centers in the US (Barst 2008). The sex ratio between female and male is approximately 2:1 in childhood (Badesch et al. 2010) and median survival in children <16 years, prior to the introduction of specific therapies for PAH, was ≤6 months (D’Alonzo et al. 1991; Barst et al. 1999). While sildenafil and bosentan have recently had language added to their labels pertaining to the pediatric population, there remain limited data on the safety and efficacy of the approved adult treatments in a pediatric population. Therapeutic guidelines for children have therefore generally followed those used in adults. Therapies currently approved for the treatment of PAH in adults, in various geographies around the world, include prostacyclin and its analogues (epoprostenol, trepostinil, iloprost, and beraprost), the endothelin receptor antagonists (bosentan and ambrisentan), and the phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil and tadalafil). Tadalafil is an orally administered, potent, and selective PDE-5 inhibitor currently approved in the United States, European Union, Canada and in Japan for the treatment of erectile dysfunction (ED), both on-demand (at doses of 5 mg, 10 mg and 20 mg) and once-daily (at doses of 2.5 mg and 5 mg), and for the treatment of pulmonary arterial hypertension (PAH) (at a dose of 40 mg daily). In adults, tadalafil is rapidly absorbed after oral administration, with maximum concentrations (Cmax) in plasma occurring at a median time of 2 hours. The rate and extent of absorption from tadalafil 10 mg and 20 mg are not influenced by food. Tadalafil is distributed into tissues, with an apparent volume of distribution of 62.6 L. Tadalafil is cleared extensively, with metabolism by cytochrome P450 (CYP) 3A4 being the major pathway. The mean terminal elimination halflife (t½) for tadalafil is 17.5 hours. Tadalafil pharmacokinetics are linear with respect to time and dose over a range of 2.5 to 20 mg. During tadalafil 20 mg once-daily dosing, steady-state plasma concentrations were attained within about 5 days and the degree of drug accumulation was about 1.6-fold. A tadalafil 40 mg single dose is rapidly absorbed, with Cmax in plasma occurring at a median time of 4 hours, and within the range of that reported following a 20 mg single dose. Following tadalafil 40 mg once-daily, the apparent clearance at steady state (CLss/F) and accumulation ratios remained stationary between Day 5 and Day 10. Increases in both Cmax and area under the concentration versus time curve (AUC) are less than proportional as the dose increases from 20 mg to 40 mg. Specifically, due to decreased bioavailability with 40 mg oncedaily doses compared to lower doses, a 2-fold change in dose from 20 mg to 40 mg results in a 48% increase in exposure. The safety and efficacy of tadalafil for the treatment of PAH in adults was investigated in a 16-week placebo-controlled study (Study H6D-MC-LVGY [LVGY]) which demonstrated that, overall, tadalafil 40 mg once-daily dosing was effective in the treatment of patients with PAH and was associated with an increase in exercise capability. Tadalafil 40 mg was well tolerated in the adult PAH patient population with a safety profile similar to that observed in the erectile dysfunction patient population. Population pharmacokinetic (PopPK) data from Study LVGY show that exposure to tadalafil is not influenced by age, cardiovascular conditions, sex, ethnicity, PAH history or duration, creatinine clearance (CC), total serum protein, weight, warfarin, or digoxin, thereby suggesting that tadalafil can be administered without regard to these factors. Concomitant bosentan therapy increased the apparent oral clearance of tadalafil by 75%, resulting in a 35% decrease in exposure in patients receiving 40 mg tadalafil. In patients with PAH not receiving concomitant bosentan, the predicted median tadalafil exposure at steady-state was 26% higher when compared to that in healthy volunteers. There were no clinically relevant differences in mean Cmax compared to healthy volunteers. The results suggest a potentially lower mean clearance of tadalafil in patients with PAH compared to healthy volunteers. An aqueous, ready-to-use suspension for oral administration of 2.0 mg/mL tadalafil has been developed for use in younger children. A relative bioavailability study (Study H6D-MC-LVIF [LVIF]) has been performed in healthy adults to investigate the relative bioavailability of one 20 mg tablet compared to a suspension containing 20 mg tadalafil. Study LVIF also assessed the pharmacokinetics of the tadalafil suspension over the 20 mg to 40 mg dose range. The results from Study LVIF demonstrated that the 20 mg suspension produced a 23% lower Cmax for tadalafil and significant delay in time of maximum observed concentration (tmax) of 1 hour compared to the 20 mg tablet. However, overall exposure to tadalafil was similar for the 20 mg suspension and tablet, with the 90% confidence intervals for the ratios falling within the bioequivalence limits of 0.80 to 1.25. Exposure to tadalafil during the absorption/distribution phase is lower for the 20 mg suspension compared to the 20 mg tablet, with AUC(0-6) and AUC(0-12) being 25% and 16% lower. Results indicated a less-than-dose-proportional increase in tadalafil exposure over the 20 mg to 40 mg dose range for the suspension formulation. Given the efficacy and safety results of tadalafil for the treatment of PAH in adults (Study LVGY), and recognizing the importance of providing prescribers and patients with recommendations reflecting tadalafil experience across developmental stages, Lilly is pursuing the development of tadalafil for the treatment of PAH in patients ≥6 months of age to <18 years of age.