TY - JOUR
T1 - Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction
T2 - An exploratory approach
AU - Sridharan, Kannan
AU - Sannala, Chenna Keshava Reddy
AU - Mallayasamy, Surulivelrajan
AU - Chaturvedula, Ayyappa
AU - Kadam, Prashant
AU - Hase, Nivrutti
AU - Shukla, Akash
AU - Gogtay, Nithya
AU - Thatte, Urmila
N1 - Publisher Copyright:
© 2019 Indian Journal of Pharmacology Published by Wolters Kluwer - Medknow.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Hepatic dysfunction
KW - Indian patients
KW - NONMEM
KW - pharmacokinetics
KW - primaquine
UR - http://www.scopus.com/inward/record.url?scp=85063425918&partnerID=8YFLogxK
U2 - 10.4103/ijp.IJP_230_16
DO - 10.4103/ijp.IJP_230_16
M3 - Article
C2 - 31031463
AN - SCOPUS:85063425918
SN - 0253-7613
VL - 51
SP - 17
EP - 24
JO - Indian Journal of Pharmacology
JF - Indian Journal of Pharmacology
IS - 1
ER -