Lopinavir dose might have to be increased during pregnancy - British HIV Association article

Lopinavir protein binding in HIV-1-infected pregnant women

FT Aweeka ¹ , A Stek ² , BM Best ³ , C Hu ⁴ , D Holland ³ , A Hermes ⁵ , SK Burchett ⁶ , J Read ⁷ , M Mirochnick ⁸ , EV Capparelli ³ and the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1026s Protocol Team

¹ University of California, San Francisco, CA, USA, ² University of Southern California, Los Angeles, CA, USA, ³ University of California, San Diego, CA, USA, ⁴ Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA, USA, ⁵ Abbott Laboratories, Abbott Park, IL, USA, ⁶ Children's Hospital Boston, Boston, MA, USA, ⁷NICHD, Bethesda, MD, USA and ⁸ BU School of Medicine, Boston, MA, USA

Correspondence: Francesca T. Aweeka, Drug Research Unit, University of California, 521 Parnassus Ave, San Francisco, CA 94143-0622, USA. Tel: +1 415 476 0339; fax: +1 415 476 0307; e-mail: faweeka@sfghsom.ucsf.edu

ABSTRACT

Background

Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and α-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ≥1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.

Methods

P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.

Results

AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96±0.16% AP vs. 0.82±0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.

Conclusions

LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.

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Accepted 23 July 2009