TY - JOUR
T1 - Protein binding of lopinavir and ritonavir during 4 phases of pregnancy
T2 - Implications for treatment guidelines
AU - Patterson, Kristine B.
AU - Dumond, Julie B.
AU - Prince, Heather A.
AU - Jenkins, Amanda J.
AU - Scarsi, Kimberly K.
AU - Wang, Ruili
AU - Malone, Stephanie
AU - Hudgens, Michael G.
AU - Kashuba, Angela D.M.
PY - 2013/5/1
Y1 - 2013/5/1
N2 - OBJECTIVE: To investigate the intraindividual pharmacokinetics (PKs) of total (protein bound plus unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100 mg/25 mg) can overcome any pregnancy-associated changes. DESIGN: Prospective longitudinal PK study. METHODS: HIV-infected pregnant antiretroviral therapy-naive and experienced women receiving LPV/RTV 400 mg/100 mg tablets twice daily. Intensive PK evaluations were performed at 20-24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100 mg/25 mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). RESULTS: Twelve women completed prespecified PK evaluations. Median (range) age was 28 (18-35) years and baseline BMI was 32 (19-41) kg/m. During pregnancy, total area under the time concentration (AUC0-12h) for LPV was significantly lower than postpartum (PK1, PK2, or PK3 vs. PK4, P = 0.005). Protein-unbound LPV AUC0-12h remained unchanged during pregnancy [PK1: 1.6 (1.3-1.9) vs. PK2: 1.6 (1.3-1.9) μg·h/mL, P = 0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3-2.1) μg·h/mL, P = 0.5]. Protein-unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08-0.15) vs. PK3: 0.12 (0.10-0.15) μg/mL, P = 0.09]. Albumin and LPV AUC0-12h fraction unbound were correlated (rs = 0.3, P = 0.03). CONCLUSIONS: Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.
AB - OBJECTIVE: To investigate the intraindividual pharmacokinetics (PKs) of total (protein bound plus unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100 mg/25 mg) can overcome any pregnancy-associated changes. DESIGN: Prospective longitudinal PK study. METHODS: HIV-infected pregnant antiretroviral therapy-naive and experienced women receiving LPV/RTV 400 mg/100 mg tablets twice daily. Intensive PK evaluations were performed at 20-24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100 mg/25 mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). RESULTS: Twelve women completed prespecified PK evaluations. Median (range) age was 28 (18-35) years and baseline BMI was 32 (19-41) kg/m. During pregnancy, total area under the time concentration (AUC0-12h) for LPV was significantly lower than postpartum (PK1, PK2, or PK3 vs. PK4, P = 0.005). Protein-unbound LPV AUC0-12h remained unchanged during pregnancy [PK1: 1.6 (1.3-1.9) vs. PK2: 1.6 (1.3-1.9) μg·h/mL, P = 0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3-2.1) μg·h/mL, P = 0.5]. Protein-unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08-0.15) vs. PK3: 0.12 (0.10-0.15) μg/mL, P = 0.09]. Albumin and LPV AUC0-12h fraction unbound were correlated (rs = 0.3, P = 0.03). CONCLUSIONS: Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.
KW - HIV
KW - lopinavir/ritonavir
KW - pharmacokinetics
KW - pregnancy
KW - protein unbound
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U2 - 10.1097/QAI.0b013e31827fd47e
DO - 10.1097/QAI.0b013e31827fd47e
M3 - Article
C2 - 23221983
AN - SCOPUS:84876296360
VL - 63
SP - 51
EP - 58
JO - Journal of Acquired Immune Deficiency Syndromes
JF - Journal of Acquired Immune Deficiency Syndromes
SN - 1525-4135
IS - 1
ER -