title: No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects.
abstract: Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, Illinois, USA Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt sale0074@umn.edu.
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, Illinois, USA.
authors.forename: Aksana Kaefer
authors.initials: AK
authors.lastname: Jones
authors.affiliation: Laboratório de Pesquisa Clínica em DST/AIDS, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Manguinhos, Rio de Janeiro, Brazil.
authors.forename: Marilia
authors.initials: M
authors.lastname: Santini-Oliveira
authors.affiliation: Saint Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom Section of Infectious Diseases, Imperial College London, London, United Kingdom.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.affiliation: Infectious Diseases Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Nilius
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, Illinois, USA.
authors.forename: Cheri Enders
authors.initials: CE
authors.lastname: Klein
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D061466:Lopinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013607:Tablets; D053719:Tandem Mass Spectrometry; D019562:Viral Load / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D013607:Tablets; D061466:Lopinavir; D019438:Ritonavir