Population pharmacokinetics and model-informed precision dosing of lamivudine in Chinese HIV-infected patients with mild and moderate impaired renal function

ABSTRACT

Background

Lamivudine is a first-line medication used for human immunodeficiency virus (HIV) treatment. To date, the population pharmacokinetics of lamivudine in Chinese HIV-infected adults have not been assessed. This study aimed to develop a population pharmacokinetic model for oral lamivudine in Chinese HIV-infected adults and to determine the optimal lamivudine dosage regimens.

Research design and methods

A total of 1113 samples, from 828 Chinese HIV-infected patients treated with lamivudine 300 mg every 24 hours, were pooled from two open-label, prospective clinical trials. A population pharmacokinetics analysis was performed using a nonlinear mixed-effects modeling method. A Monte Carlo simulation was conducted to optimize lamivudine dosing.

Results

A two-compartment model adequately described the population pharmacokinetics of lamivudine. The typical population estimate for apparent clearance was 28.3 L/h. Creatinine clearance was identified as a significant factor influencing apparent clearance. According to the Monte Carlo simulation, patients with creatinine clearance between 50 and 70 mL/min should receive lamivudine 200 mg every 24 h or 300 mg every 36 h, to achieve optimal lamivudine exposure.

Conclusions

No obvious ethnic differences were observed in lamivudine pharmacokinetics between Chinese and Caucasian populations. Additionally, a model-informed dosage regimen is recommended for patients with impaired renal function.

KEYWORDS:

• Lamivudine
• population pharmacokinetics
• HIV
• renal impairment
• Monte Carlo simulation
• Chinese population

Acknowledgments

We thank Editage (www.editage.cn) for English language editing.

Author contributions

H Wen: methodology, formal analysis, validation, visualization, writing – original draft, writing - review & editing, and funding acquisition. Y Lin: methodology, validation, writing – original draft. J Wang: source, writing - review & editing. L Zhang: source. T Sun: methodology, data curation. F Xu: data curation, writing - review & editing. M Zhang: conceptualization, formal analysis, writing -review & editing. L Liu and R Zhang: source, writing -review & editing. X Liu: methodology, data curation. X Meng: data curation, writing - review & editing. Y Xing: data curation, writing - review & editing. H Lu: funding acquisition, writing -review & editing. Z Jiao: methodology, formal analysis, writing - original draft, writing - review & editing. L Zhang: funding acquisition, conceptualization, methodology, supervision, writing - original draft, writing -review & editing.

Funding

This study was supported by Shanghai clinical research center for infectious disease (HIV/AIDS) (20MC1920100), National Science and Technology Program (China grant, no. 2017ZX09304027), and National Science and Technology Program for the treatment of HIV-TB co-infection (2017ZX10202101-002), the Key Issues of Shanghai Municipal Commission of Health and Family Planning (201640005), and Shanghai ‘Rising Stars of Medical Talents’ Youth Development Program-Youth Medical Talents: Clinical Pharmacist Program (SHWSRS(2021)_099).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethics approval

The ethical approval has been obtained from the ethics committee of the Shanghai Public Health Clinical Center (No. 201[3] Ethics (010), No. 2020-S161-01). All human research procedures followed were in accordance with the standards set forth in the Declaration of Helsinki Principles of 1975, as revised in 2013 (http:/ethics. iit.Edu.ecodes/node/3931).

Abbreviations

HIV,	=	Human immunodeficiency virus;
PPK,	=	population pharmacokinetics;
ALT,	=	alanine aminotransferase;
AST,	=	aspartate aminotransferase;
AUC,	=	area under concentration-time curve;
BMI,	=	body mass index;
BSV,	=	between-subject variability;
BW,	=	body weight;
CCR,	=	creatinine clearance;
CL/F,	=	apparent clearance;
CWRES,	=	conditional weighted residual error;
LC-MS,	=	liquid chromatography-mass spectrometry;
NRTI,	=	nucleoside analog reverse transcriptase inhibitor;
PK,	=	pharmacokinetics;
RUV,	=	residual unexplained variability;
SCr,	=	serum creatinine;
TBIL,	=	total bilirubin;
Vd/F,	=	apparent volume of distribution;
VPC,	=	visual predictive check

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17512433.2022.2078306