Pharmacokinetics and safety of tadalafil in a paediatric population with pulmonary arterial hypertension: A multiple ascending‐dose study

Small, David S.; Ferguson-Sells, Lisa; Dahdah, Nagib; Bonnet, Damien; Landry, John; Li, Baohui

doi:10.1111/bcp.14039

Cited by 10 publications

(33 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…13 Recent pharmacokinetic studies have shown adult exposure levels can be obtained in children and tadalafil levels are lower in combination with bosentan, but remain in the expected range. 7 The overall safety profile of tadalafil, including most common TEAEs, observed in the current study was consistent with previous knowledge. The overall incidence of AEs was higher in the tadalafil group compared with placebo.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, Small et al. (2019) 7 recently also reported tadalafil 40 mg QD for patients ≥40 kg, and 20 mg QD for patients <40 kg and ≥2 years old have an acceptable safety profile in pediatric patients with PAH consistent with the safety profile in adult patients with PAH. 4 …”

Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double‐blind placebo‐controlled study

et al. 2021

Self Cite

View full text Add to dashboard Cite

Objective: This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH). Methods: This phase-3, international, randomized, multicenter (24 weeks double-blind placebo controlled period; 2-year, open-labelled extension period), add-on (patientâs current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with PAH. Patients received tadalafil 20 mg or 40 mg based on their weight (Heavy-weight: â¥40 kg; Middle-weight: â¥25â<40 kg) or placebo orally QD for 24 weeks. Primary endpoint was change from baseline in 6-minute walk (6MW) distance in patients aged â¥6 years at Week 24. Sample size was amended from 134 to â¥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results: Patient demographics and baseline characteristics (N=35; tadalafil=17; placebo=18) were comparable between treatment groups; median age was 14.2 years (6.2 to 17.9 years) and majority (71.4%, n=25) of patients were in HW cohort. Least square mean (SE) changes from baseline in 6MW distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 [20.41] vs 36.60 [20.78] meters; placebo-adjusted mean difference [SD] 23.88 [29.11]). Safety of tadalafil treatment was as expected without any new safety concerns. During study period 1, two patients (1 in each group) discontinued due to investigatorâs reported clinical worsening, and no deaths were reported. Conclusions: The statistical significance testing was not performed between the treatment groups due to low sample size, however, the study results show positive trend in improvement in non invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with PAH. Safety of tadalafil treatment was as expected without any new safety signals.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 83%

See 1 more Smart Citation

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double‐blind placebo‐controlled study

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

“…A phase Ib/II, multiple ascending dose study (H6D-MC-LVIG [LVIG]) [5] was conducted to evaluate the safety and pharmacokinetics (PK) of tadalafil in planned PAH patients aged 6 months to < 18 years, with a goal to mimic typical drug exposures in adults with PAH and determine doses for further investigation in phase III. A previous publication discussed safety and noncompartmental analyses for this trial [5], whereas the focus of this article is on the results of the population PK (PopPK) analysis. The purpose of the PopPK analysis was to characterize tadalafil PK across the range of body weights and ages enrolled in the study and in each cohort; to evaluate the effect of various covariates such as age, body weight, sex, and endothelin receptor antagonist (ERA) use on tadalafil exposure; and to predict appropriate dose(s) in subsequent pediatric studies of tadalafil.…”

Section: Introductionmentioning

confidence: 99%

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

Ferguson-Sells

Mendizábal

et al. 2021

Clin Pharmacokinet

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Pediatric Population Pharmacokinetic Modeling and Exposure–Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data

Okour¹,

Thapar²,

Farrell³

et al. 2023

The Journal of Clinical Pharma

View full text Add to dashboard Cite

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6‐minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady‐state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2‐compartment model including the effect of body weight (allometric scaling), first‐order absorption and elimination, and absorption lag time. Steady‐state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration‐time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6‐minute walking distance or incidence of ambrisentan‐related adverse events in pediatric patients. The similar ambrisentan exposure and exposure–response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body‐weight–based dosing in the pediatric population with PAH.

show abstract

Pharmacokinetics and safety of tadalafil in a paediatric population with pulmonary arterial hypertension: A multiple ascending‐dose study

Cited by 10 publications

References 15 publications

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double‐blind placebo‐controlled study

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double‐blind placebo‐controlled study

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

Pediatric Population Pharmacokinetic Modeling and Exposure–Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data

Contact Info

Product

Resources

About