Indian journal of pharmacology · 2019
Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction: An exploratory approach.
Контролируемое клиническое исследованиеСтатьяНазвание и аннотация: Перевод в очереди
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Sridharan Kannan, Sannala Chenna Keshava Reddy, Mallayasamy Surulivelrajan, Chaturvedula Ayyappa, Kadam Prashant, Hase Nivrutti, Shukla Akash, Gogtay Nithya, Thatte Urmila
Аннотация
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.
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.