Why the study?
Limited information is available regarding treprostinil disposition and its use in special populations such as elderly, paediatric, and pregnant patients.
Can a physiologically based pharmacokinetic model accurately predict the disposition of treprostinil after intravenous and oral administration in healthy volunteers and patients with hepatic impairment?
Can a physiologically based pharmacokinetic model accurately predict the disposition of treprostinil after intravenous and oral administration in healthy volunteers and patients with hepatic impairment?
A newly developed physiologically based pharmacokinetic model successfully predicts treprostinil disposition for IV and oral formulations, enabling extrapolation to special populations such as those with hepatic impairment.
Answers are grounded in this paper and cite their sources.
May inform treprostinil dosing in special PAH populations; leaves open prospective validation.
AIMS: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary arterial pressure, resulting in right ventricular overload, right heart failure and eventually death. Treprostinil is a prostacyclin analogue that is used in the treatment of PAH. As an orphan drug, limited information is available regarding its disposition and its use in special populations such as elderly, paediatric and pregnant patients. The objective of the current study was to develop a robust physiologically based pharmacokinetic (PBPK) model for treprostinil intravenous injection and extended-release tablet as the first step to optimize treprostinil pharmacotherapy in patients. METHODS: PBPK model was built using Simcyp simulator which integrated physicochemical properties, observed or predicted parameters for drug absorption, distribution and elimination for treprostinil, and population specific physiological characteristics. Three clinical trials after intravenous infusion and nine studies after oral administration of treprostinil extended-release tablet in healthy volunteers were used to develop and validate the model. The simulated PK profiles were compared with the observed data. Extrapolation of the model to patient populations including patients with hepatic impairment was conducted to validate the predictions. RESULTS: percentile interval of the prediction. Most of the percentage error in the PK parameters were within ±50% of the corresponding observed parameters. The developed model predicted the lung exposure of treprostinil to be approximately 0.17 times of concentration in plasma. CONCLUSION: Predicted absorption, distribution, and metabolic enzyme kinetics gave an insight into the disposition of treprostinil in humans. Extrapolation of the established model to patient populations with hepatic impairment successfully documented the model reliability. The developed model has the potential to be used in the PK predictions in other special patient populations with different demographic, physiological and pathological characteristics.
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Wu et al. (2021) studied this question.
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