Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction

An exploratory approach

Kannan Sridharan, Chenna Keshava Reddy Sannala, Surulivelrajan Mallayasamy, Ayyappa Chaturvedula, Prashant Kadam, Nivrutti Hase, Akash Shukla, Nithya Gogtay, Urmila Thatte

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)17-24
Number of pages8
JournalIndian Journal of Pharmacology
Volume51
Issue number1
DOIs
Publication statusPublished - 01-01-2019

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Primaquine
Pharmacokinetics
Kidney
Liver
Population
Healthy Volunteers
Software

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Sridharan, Kannan ; Sannala, Chenna Keshava Reddy ; Mallayasamy, Surulivelrajan ; Chaturvedula, Ayyappa ; Kadam, Prashant ; Hase, Nivrutti ; Shukla, Akash ; Gogtay, Nithya ; Thatte, Urmila. / Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction : An exploratory approach. In: Indian Journal of Pharmacology. 2019 ; Vol. 51, No. 1. pp. 17-24.
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abstract = "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 {\circledR} 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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Sridharan, K, Sannala, CKR, Mallayasamy, S, Chaturvedula, A, Kadam, P, Hase, N, Shukla, A, Gogtay, N & Thatte, U 2019, 'Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction: An exploratory approach', Indian Journal of Pharmacology, vol. 51, no. 1, pp. 17-24. https://doi.org/10.4103/ijp.IJP_230_16

Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction : An exploratory approach. / Sridharan, Kannan; Sannala, Chenna Keshava Reddy; Mallayasamy, Surulivelrajan; Chaturvedula, Ayyappa; Kadam, Prashant; Hase, Nivrutti; Shukla, Akash; Gogtay, Nithya; Thatte, Urmila.

In: Indian Journal of Pharmacology, Vol. 51, No. 1, 01.01.2019, p. 17-24.

Research output: Contribution to journalArticle

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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

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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.

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