Population Pharmacokinetics of Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension: A Combined Adult/Pediatric Model

Abstract

Background: Tadalafil 40 mg once daily is approved for adult patients with pulmonary arterial hypertension (PAH). To investigate and potentially fulfill an unmet need in pediatric patients with PAH, pharmacokinetic (PK) data were explored in a pediatric phase Ib/II study and pooled with prior phase III (pulmonary arterial hypertension and response to tadalafil [PHIRST-1]) adult data to develop the first population PK model for tadalafil in pediatric patients with PAH.

Methods: H6D-MC-LVIG (NCT01484431) was an open-label, multicenter, multiple ascending dose study in pediatric patients with PAH, while PHIRST-1 was a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel design study in adults with PAH who received one of five treatments (tadalafil 2.5, 10, 20, or 40 mg, or placebo orally, once daily). PK data from the studies were pooled to develop a pediatric population PK model for tadalafil that characterized relationships among dose, exposure, and the effects of covariates with an aim to develop a population PK model that could simulate concentration-time profiles and assess exposure-matched dosing strategies in a pediatric PAH population.

Results: In line with the observed data, modeling and simulation demonstrated that the doses studied in the pediatric population produced area under the concentration-time curves (AUCs) within the range of those associated with improved exercise ability in adults with PAH. The analyses included 1430 observations from 305 adult patients (PHIRST-1: 69 males and 236 females, 1102 observations) and 19 pediatric patients (LVIG: 6 males and 13 females, 328 observations) who received tadalafil once daily at different dose levels. The best-fit base model retained an effect of weight on apparent volume of distribution (V/F), fixed to the allometric scaling value of 1, and did not include an effect of weight on apparent clearance (CL/F). Other covariate effects were that bosentan increased CL/F, V/F decreased with decreasing body weight, and bioavailability (F) decreased with increasing dose and decreasing age. The PK model reliably predicted the observed concentrations and overall variability evident from the overlap of the individual observed concentrations with the distributions of simulated concentrations.

Conclusions: A one-compartment model parameterized in terms of F, absorption rate constant, CL/F, and V/F described the data well. The model demonstrated that plasma tadalafil concentrations in pediatric patients aged 2 to < 18 years were similar to those in adults at similar doses, and confirmed that dosing of 40 mg once daily in pediatric patients with a bodyweight ≥ 40 kg, and a dose of 20 mg once daily in patients with a body weight < 40 kg and aged ≥ 2 years are suitable for phase III evaluation.

Trial registration number (date of registration): LVIG: ClinicalTrials.gov identifier: NCT01484431 (2 December 2011). PHIRST-1: ClinicalTrials.gov identifier: NCT00125918 (2 August 2005).

Conflict of interest statement

Lisa Ferguson-Sells and Baohui Li are employees of Eli Lilly and Company and own stocks. David Small and Nieves Velez de Mendizabal are former employees of Eli Lilly and Company. NVM is an employee of Metrum Research Group, Tariffville, CT, USA, and DS is an employee of Karuna Therapeutics, Boston, MA, USA.

© 2021. The Author(s).

Figures

Fig. 1

Model-estimated pediatric PK parameters and relevant covariates from LVIG. Effect of a bosentan use on CL/F; b body weight on V/F; c dose on F; and d age on F. The effect of bosentan on CL/F and the effect of body weight on V/F were not affected by dose; high- and low-dose data overlap, therefore only the high dose is visible in plots (a) and (b). Open and solid circles depict individual data points, and lines depict a linear regression through the points. PK pharmacokinetic, CL/F apparent clearance, V/F apparent volume of distribution, F bioavailability

Fig. 2

a Prediction-corrected VPC for the final population PK model stratified by the LVIG and PHIRST-1 studies (top row), and further stratified by weight category for LVIG and by dose for PHIRST-1 (bottom row). Black open circles represent individual observed concentrations. The solid black line depicts the median of observed data, while the orange shaded area represents the 95% confidence interval around the median of the simulated data. The dashed lines represent the 10th and 90th percentiles of observed concentrations, while the grey shaded areas represent simulated 95% confidence intervals. b Goodness-of-fit plots for the final population PK model. PK pharmacokinetic, VPC visual predictive check, DDI daily dose in milligrams, GRP pediatric weight category as follows: 1, heavy-weight ≥ 40 kg; 2, middle-weight 25 to < 40 kg; and 3, light-weight < 25 kg. Tadalafil concentration units are ng/mL

Fig. 3

The boundary of the box closest to zero indicates the 25th percentile, a line within the box marks the median, and the boundary of the box farthest from zero indicates the 75th percentile. Whiskers (error bars) above/below the box indicate the 90th/10th percentiles, and open circles represent the 5th and 95th percentiles. Simulated adult data from PHIRST-1; simulated pediatric data from LVIG; heavy-weight patients weigh >40 kg, mid-weight patients weigh 25–40 kg, and light-weight weigh AUC area under the curve, AUCss steady-state area under the curve, Mid-wt mid weight, QD once daily, wt weight

Fig. 4

Simulated tadalafil concentration–time profiles over a dosing interval at steady-state in the three pediatric weight cohorts and in adults with (left panel) or without (right panel) concomitant bosentan a at proposed phase III doses for children aged ≥ 2 years; b with adult and all pediatric patients taking 40 mg of tadalafil; or c light-weight cohort illustrating overlap to adult concentrations during 20 or 40 mg once-daily dosing. Lines represent the predicted average concentrations at steady state based on 1250 simulations in each cohort. Pediatric cohorts were simulated using the PopPK model developed in LVIG, while the profile in adults was simulated using the PopPK model from PHIRST-1. ‘Time’ on the x-axis is time from the first dose, hence these profiles represent steady-state profiles after the eighth once-daily dose. Shaded regions represent the 90% prediction interval. LVGY is another name for the PHIRST-1 study. PopPK population pharmacokinetics, QD once daily