Individualized Absorption Models in Population Pharmacokinetic Analyses.
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ABSTRACT:
SUBMITTER: Jaber MM
PROVIDER: S-EPMC7306615 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Individualized Absorption Models in Population Pharmacokinetic Analyses.
Jaber Mutaz M MM Al-Kofahi Mahmoud M Sarafoglou Kyriakie K Brundage Richard C RC
CPT: pharmacometrics & systems pharmacology 20200521 6
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Project description:BackgroundSalbutamol, a short-acting β2-agonist used in asthma treatment, is available in multiple formulations, including inhalers, nebulizers, oral tablets, and intravenous, intramuscular, and subcutaneous routes. Each formulation exhibits distinct pharmacokinetic (PK) and pharmacodynamic (PD) profiles, influencing therapeutic outcomes and adverse effects. Although asthma management predominantly relies on inhaled salbutamol, understanding how these formulations interact with patient-specific characteristics could improve personalized medicine approaches, potentially uncovering the therapeutic benefits of alternative formulations for an individual patient. Herein, this study aims to analyze how covariates-such as age, weight, gender, body surface area (BSA), cytochrome P450 (CYP) expression, race, and health status-affect the therapeutic regime of orally administered salbutamol using population PK (popPK) modeling. The final model is intended as a tool to support the selection of optimal formulation and dosage regimen based on individual patient profiles.MethodsA dataset of 40 virtual patients derived from a physiologically based PK (PBPK) model of oral salbutamol was included in the popPK model.ResultsA two-compartment model with first-order elimination and absorption, with a transit compartment, best described the plasma concentration-time profile following a 4 mg dose. Relationships were identified between gender and mean transit time (Mtt) and clearance (Cl), as well as the effects of weight and BSA on the volume of distribution of the central compartment (V1) and Cl, and a significant impact of health status on Cl.ConclusionsDespite current contraindications for oral salbutamol, our findings suggest that certain individuals, particularly children, may benefit from oral treatment over inhalation. We also identified individual characteristics associated with increased salbutamol toxicity risk, indicating the need for dose adjustment or alternative administration. This study further highlights the potential of popPK modeling in personalized therapy through a fully in silico approach.
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Project description:Background and objectiveParoxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan.MethodsPooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly.ResultsThe population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful.ConclusionsThe approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.
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