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Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1

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Abstract

The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860 h−1, and the lag time was predicted at 0.311 h. Oral bioavailability was estimated to be 68.8% at dose of 300 mg, 62.7% at dose of 400 mg, and 47.1% at dose of 800 mg. The creatinine clearance significantly influenced on the oral clearance (P < 0.005) and ABCB1 2677G > T/A genotypes significantly influenced on the absorption rate constant (P < 0.05) of gabapentin. However, ABCB1 1236C > T and 3435C > T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G > T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2017RIDIAB04035667).

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Author notes

  1. Phuong Tran and Hee-Doo Yoo contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Institute of Bioequivalence and Bridging Study, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea

    Phuong Tran, Hee-Doo Yoo, Lien Ngo & Yong-Bok Lee

  2. College of Pharmacy, CHA University, 335, Pangyo-ro, Bungdang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea

    Hea-Young Cho

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  1. Phuong Tran
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Appendix

Appendix

Extraction of the codes used in modeling drug absorption

$PK

 
 

; ABCB1-DEFINITION START

IF(EX21.EQ. 1) COEX21 = 1

; Subjects of GG group

IF(EX21.EQ. 2) COEX21 = 1

; Subjects of GT, GA group

IF(EX21.EQ. 3) COEX21 = 1 + THETA(8)

; Subject of TT, AT group

 

; ABCB1-DEFINITION END

TVCL

= THETA(1)* (CRCL/106.3)**THETA(7)

; Clearance

CL

= TVCL * EXP(ETA(1))

 

TVV

= THETA(2)

; Volume of distribution

V

= TVV * EXP(ETA(2))

 

TVKA

= THETA(3)* COEX21

; Absorption rate constant

KA

= TVKA * EXP(ETA(3))

 

TVLG

= THETA(4)

; Lag time

ALAG1

= TVLG * EXP(ETA(4))

 

IMAX

= THETA(5)

; Maximum inhibition of dose on bioavailability

ID50

= THETA(6) * EXP(ETA(5))

; Dose which produces 50% of maximum inhibition effect

F1

= 1 – IMAX * DOSE/(ID50 + DOSE)

; Bioavailability

S2

= V

; Scaling factor

$ERROR

FLAG = 0

IF (F. Equation 0) FLAG = 1

IPRED = LOG(F + FLAG)

Y = (1 − FLAG)*IPRED + EPS(1)

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Tran, P., Yoo, HD., Ngo, L. et al. Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1 . J Pharmacokinet Pharmacodyn 44, 567–579 (2017). https://doi.org/10.1007/s10928-017-9549-6

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