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. 2024 Oct 1;79(10):2570-2574.
doi: 10.1093/jac/dkae259.

Lamivudine dosing for preterm infants exposed to HIV: a population pharmacokinetic modelling and simulation study

Adrie Bekker  1 , Edmund V Capparelli  2 , Mark Mirochnick  3 , Diana F Clarke  4 , Mark F Cotton  1 , Roger Shapiro  5   6 , Katie McCarthy  7 , Jack Moye  8 , Avy Violari  9 , Kulkanya Chokephaibulkit  10 , Elaine Abrams  11 , Martina Penazzato  12 , Theodore D Ruel  13 , Tim R Cressey  14
Affiliations

Lamivudine dosing for preterm infants exposed to HIV: a population pharmacokinetic modelling and simulation study

Adrie Bekker et al. J Antimicrob Chemother. .

Abstract

Objectives: To develop a pragmatic twice daily lamivudine dosing strategy for preterm infants from 24 to 37 completed weeks of gestation.

Methods: Data were combined from eight pharmacokinetic studies in neonates and infants receiving lamivudine oral solution. A population pharmacokinetic model was developed using non-linear mixed effects regression. Different lamivudine dosing strategies, stratified by gestational age at birth (GA) bands, were simulated in a virtual population of preterm infants, aimed at maintaining lamivudine drug exposures (AUC0-12) within a reference target range of 2.95 to 13.25 µg·h/mL, prior to switching to WHO-weight band doses when ≥4 weeks of age and weighing ≥3 kg.

Results: A total of 154 infants (59% female) contributed 858 lamivudine plasma concentrations. Median (range) GA at birth was 38 (27-41) weeks. At the time of first pharmacokinetic sampling infants were older with median postnatal age (PNA) of 6.3 (0.52-26.6) weeks. Lamivudine concentrations were described by a one-compartment model, with CL/F and V/F allometrically scaled to weight. Maturation of CL/F was described using an Emax model based on PNA. CL/F was also adjusted on GA to allow extrapolation for extreme prematurity. Simulations predicted an optimal lamivudine dosing for infants GA ≥24 to <30 weeks of 2 mg/kg twice daily from birth until weighing 3 kg; and for GA ≥30 to <37 weeks, 2 mg/kg twice daily for the first 4 weeks of life, followed by 4 mg/kg twice daily until weighing 3 kg.

Conclusions: Model-based predictions support twice daily pragmatic GA band dosing of lamivudine for preterm infants, but clinical validation is warranted.

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Figures

Figure 1.
Figure 1.
Predicted lamivudine (3TC) geometric mean AUC0-12 through 12 weeks of life: GA 24 to <30 weeks: 2 mg/kg twice daily from birth; GA ≥30 to <37 weeks: 2 mg/kg twice daily for the first 4 weeks of life, then 4 mg/kg twice daily. Dotted lines represent lamivudine geometric mean AUC0-12 target range. Infants reaching ≥3 kg and aged ≥4 weeks switch to follow WHO weight-band dosing recommendations and are not included in the figure. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
See this image and copyright information in PMC

References

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