Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction: An exploratory approach
By: Sridharan, Kannan
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Contributor(s): Sannala, Chenna Keshava Reddy.
Publisher: Mumbai Wolter Kluwer 2019Edition: Vol.51(1), Jan-Feb.Description: 17-24p.Subject(s): PHARMACOLOGYOnline resources: Click here
In:
Indian Journal of PharmacologySummary: OBJECTIVES: We attempted to develop a population pharmacokinetic model for primaquine (PQ) and evaluate the effect of renal and hepatic dysfunction on PQ pharmacokinetics.MATERIALS AND METHODS: The data were collected from a prospective, nonrandomized clinical study in healthy volunteers and patients with mild‑moderate hepatic dysfunction and renal dysfunction. Model development was conducted using NONMEM® software, and parameter estimation was conducted using first‑order conditional estimation with interaction method.RESULTS: Final data included a total of 53 study participants (13 healthy individuals, 12 with mild hepatic dysfunction, 6 with moderate hepatic dysfunction, and 22 with renal dysfunction) with 458 concentrations records. Absorption rate constant (Ka) was constrained to be higher than elimination rate constant to avoid flip‑flop situation. Mild hepatic dysfunction was a significant covariate on volume of distribution, and it is approximately three folds higher compared to other subjects. Fixed effects parameter estimates of the final model – absorption rate constant (Ka), volume of distribution (V), and clearance (CL) – were 0.95/h, 498 L, and 39 L/h, respectively. Between‑subject variability estimates (% CV) on Ka, V, and CL were 77, 66, and 65, respectively. Residual error was modeled as combination error model with the parameter estimates for proportion error 12% CV and additive error (standard deviation) 1.5 ng/ml.CONCLUSION: Population pharmacokinetic modeling showed that the volume of distribution of PQ in subjects with moderate hepatic dysfunction increases approximately three folds resulting in a significantly lower plasma concentration
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School of Pharmacy Archieval Section | Not for loan | 2020840 |
OBJECTIVES: We attempted to develop a population pharmacokinetic model for primaquine (PQ) and evaluate the effect of renal and hepatic dysfunction on PQ pharmacokinetics.MATERIALS AND METHODS: The data were collected from a prospective, nonrandomized clinical study in healthy volunteers and patients with mild‑moderate hepatic dysfunction and renal dysfunction. Model development was conducted using NONMEM® software, and parameter estimation was conducted using first‑order conditional estimation with interaction method.RESULTS: Final data included a total of 53 study participants (13 healthy individuals, 12 with mild hepatic dysfunction, 6 with moderate hepatic dysfunction, and 22 with renal dysfunction) with 458 concentrations records. Absorption rate constant (Ka) was constrained to be higher than elimination rate constant to avoid flip‑flop situation. Mild hepatic dysfunction was a significant covariate on volume of distribution, and it is approximately three folds higher compared to other subjects. Fixed effects parameter estimates of the final model – absorption rate constant (Ka), volume of distribution (V), and clearance (CL) – were 0.95/h, 498 L, and 39 L/h, respectively. Between‑subject variability estimates (% CV) on Ka, V, and CL were 77, 66, and 65, respectively. Residual error was modeled as combination error model with the parameter estimates for proportion error 12% CV and additive error (standard deviation) 1.5 ng/ml.CONCLUSION: Population pharmacokinetic modeling showed that the volume of distribution of PQ in subjects with moderate hepatic dysfunction increases approximately three folds resulting in a significantly lower plasma concentration
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