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
StatePublished - 1 Jan 2019

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Primaquine
Pharmacokinetics
Kidney
Liver
Population
Healthy Volunteers
Software

Keywords

  • Hepatic dysfunction
  • Indian patients
  • NONMEM
  • pharmacokinetics
  • primaquine

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

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.

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