The target lopinavir AUC0-12 during pregnancy was at least 52 mcg·hr·mL−1, the estimated 10th percentile AUC0-12 based on available data from non-pregnant adults.9 The 50th percentile lopinavir AUC0-12 in non-pregnant adults taking capsules is 82.8 mcg·hr·mL−1.9 Nine of the 11 (82%) subjects studied during the second trimester exceeded the 10th percentile AUC0-12 target, compared with 30 of 33 (91%) third trimester subjects and all 27 (100%) postpartum subjects (Fig. 2). Lopinavir concentration 12 hours after the witnessed dose (evening trough) exceeded 1.0 mcg/mL in all subjects during pregnancy and postpartum. The predose concentration (morning trough) was below 1.0 mcg/mL in 2 subjects at the second trimester, 2 different subjects at the third trimester, and another 2 different subjects at the postpartum visit.
The geometric mean third trimester/postpartum lopinavir AUC0-12 ratio was 0.73 (90% CI, 0.63 to 0.84) (Fig. 2; Table 3). The geometric mean third trimester/postpartum lopinavir and ritonavir oral clearance and apparent volume of distribution ratios fell completely outside of (above) the limits of 0.8 and 1.25, showing that third trimester CL/F and Vd/F were higher than postpartum. Within-subject comparisons of AUC0-12, CL/F, Vd/F, C min, C max, and C 12h showed that postpartum lopinavir exposure was higher and CL/F was lower than in the third trimester (P ≤ 0.05 for all comparisons), even though the postpartum dose was 33% lower than the third trimester dose.
The lopinavir geometric mean AUC0-12 ratios of second trimester/third trimester and second trimester/postpartum were 0.77 (90% CI: 0.64 to 0.92) and 0.51 (90% CI: 0.42 to 0.63), respectively. Within-subject comparisons of AUC0-12, Vd/F, C min, C predose, C 12h, and t ½ were significantly lower in the second trimester compared with the third trimester (P < 0.05). Within-subject comparisons of AUC0-12, Cl/F, C min, C max, C predose, C 12h, and t ½ also showed significantly lower lopinavir exposure in the second trimester compared with postpartum (P < 0.05). For ritonavir, similar to lopinavir, the third trimester AUC0-12, C min, and C max were lower and CL/F and Vd/F were higher than at the postpartum visit (P ≤ 0.05 for all comparisons). The second trimester ritonavir AUC0-12, C predose, C 12h, and t ½ were also lower than the third trimester and postpartum values (P ≤ 0.05).
The 1-compartment analysis yielded similar lopinavir exposure patterns to the noncompartmental analysis. The 1-compartment median (range) second trimester, third trimester, and postpartum CL/F values were 3.9 L/hr (2.9-6.5 L/hr), 4.3 L/hr (0.02-11.6 L/hr), and 2 L/hr (0.4-4.9 L/hr), respectively. The corresponding Vd/F estimated values were 30 L (17-48 L), 35 L (20-128 L), and 21 L (11-33 L).
Maternal plasma and umbilical cord samples were collected at delivery for 26 subjects. One pair was below the assay detection limit in both the maternal and umbilical cord samples.
The median (range) maternal and cord blood lopinavir concentrations were 5.2 mcg/mL (<0.091-12.2 mcg/mL) and 1 mcg/mL (<0.091-4.2 mcg/mL), respectively. The median (range) cord blood/maternal sample concentration ratio was 0.2 (0.04-0.97). A single subject had cord blood concentrations almost equal to the maternal sample concentrations (cord blood lopinavir = 1.8 mcg/mL, maternal plasma lopinavir = 1.9 mcg/mL, ratio = 0.97); all other subjects had less than 60% of the maternal lopinavir concentration detected in the cord blood.
Our first study of lopinavir/ritonavir analyzed complete pharmacokinetic profiles in 17 US women taking standard doses of the soft-gel capsules (3 capsules-400/100 mg twice daily) during the third trimester and postpartum.4 Standard dosing with the capsule formulation resulted in third trimester lopinavir plasma concentrations and AUCs that were approximately 50% lower than those seen in nonpregnant adults, but 6 week postpartum lopinavir plasma exposure equivalent to that seen in nonpregnant adults.4 Trough concentrations during the third trimester with standard capsule dosing were below 1000 ng/mL, the usual standard used in therapeutic drug monitoring programs for antiretroviral-naive patients, in 2 of 17 women (12%). Other studies of standard dosing with lopinavir/ritonavir soft-gel capsules in pregnant women have looked only at trough concentrations and have found subtherapeutic values in 6%-25% of third trimester pregnant women receiving standard dosing with lopinavir/ritonavir soft-gel capsules.10-13
Our follow-up study described lopinavir/ritonavir complete pharmacokinetic profiles after an increased dose of 4 capsules (533/133 mg twice daily) during the third trimester through 2 weeks postpartum.5 These subjects had a median third trimester AUC of 87.5 mcg·hr·mL−1, nearly equal to the 50th percentile lopinavir AUC in non-pregnant historical controls of 82.8 mcg·hr·mL−1.9,14 None of the third trimester subjects had excessive lopinavir exposure on this higher dose, and only a few had a lopinavir AUC below the target of the 10th percentile AUC in nonpregnant adults. Median second trimester AUC was lower than expected (57.3 mcg·hr·mL−1), with 3 of 8 subjects below the nonpregnant 10th percentile. However, median lopinavir AUC at 2 weeks postpartum on the increased capsule dose was nearly double that seen during the third trimester, suggesting that by 2 weeks postpartum, the pregnancy-related changes in lopinavir disposition that result in decreased plasma concentrations have resolved.
Lopinavir/ritonavir soft-gel capsules are no longer available and have been replaced by a tablet formulation. Studies of standard lopinavir/ritonavir doses with the tablet in both nonpregnant and pregnant adults report similar overall exposure compared with the capsule (tablet AUC is ∼18% higher than capsule) but with less variability.15,16 This current study reports lopinavir/ritonavir full pharmacokinetic profiles with standard doses of 2 tablets (lopinavir 400 mg/ritonavir 100 mg) twice daily in the second trimester and at 2 weeks postpartum and with an increase to 150% of the standard dose by using 3 tablets (lopinavir 600 mg/ritonavir 150 mg) twice daily during the third trimester. Overall exposure was lowest in the second trimester. With the increased dose in the third trimester, lopinavir AUC was equivalent to that seen in nonpregnant adults taking standard doses of the tablet [96 mcg·hr·mL−1 in this study versus 98 mcg·hr·mL−1 (18% higher than 82.8 mcg·hr·mL−1)]. A striking finding of our study is that lopinavir exposure with the increased dose of 3 tablets during the third trimester of pregnancy is still lower than that seen in these same women on the standard dose of 2 tablets at 2 weeks postpartum. Second trimester lopinavir exposure on standard doses was significantly lower than that seen postpartum in these women by both within-subject comparisons and bioequivalence standards (geometric mean ratios and CIs). As expected, ritonavir exposure followed similar patterns.
Lopinavir is metabolized primarily by cytochrome P450 3A4. Induction of this pathway during pregnancy likely contributes to the observed decreased lopinavir exposure. Cytochrome 3A4 induction has been documented previously in pregnant women; 1 recent study demonstrated 35% increased cytochrome P450 3A activity throughout pregnancy.17 Decreased lopinavir exposure during pregnancy could also be explained by pregnancy-related changes in lopinavir absorption or inadequate ritonavir boosting. Alterations in gastrointestinal function with pregnancy may have altered lopinavir or ritonavir absorption. Lopinavir is also a substrate for the drug transporter p-glycoprotein, an inducible protein that limits the oral bioavailability of substrates. Thus, decreased oral bioavailability of lopinavir could be a result of increased intestinal p-glycoprotein activity during pregnancy. Without an intravenous lopinavir preparation for comparison, the relative contribution of changes in lopinavir bioavailability versus intrinsic clearance cannot be determined.
Lopinavir is highly bound (98%-99%) to plasma proteins, including albumin and alpha-1 acid glycoprotein (AAG), with its affinity to AAG higher than its affinity to albumin.14 As with all highly bound drugs, small changes in protein binding may have a large effect on the concentration of free (unbound) drug, which is the pharmacologically active moiety. Protein binding may be reduced during pregnancy due to dilutional decreases in plasma protein concentrations and competitive inhibition from corticosteroid hormones.18,19 We have recently reported data describing lopinavir protein binding during pregnancy and postpartum using samples from subjects enrolling in our 2 previous studies.20 Lopinavir protein binding was reduced during pregnancy compared with postpartum, resulting in a 17% increase in the free fraction of lopinavir during the third trimester. The reduction in lopinavir protein binding correlated with lower AAG concentrations observed in the third trimester. A reduction in protein binding of this magnitude will compensate for only a portion of the decrease in lopinavir exposure associated with pregnancy.
The clinical significance of the decreased lopinavir total concentrations with standard dosing during pregnancy is uncertain. However, the risk of virologic breakthrough with low protease inhibitor trough concentrations is a concern, especially for treatment-experienced individuals.21-24 In our 3 studies of lopinavir during pregnancy, 6%, 12%, and 12% (this study) of subjects had detectable viral loads at delivery.4,5 Four other cohorts of HIV-infected pregnant women treated with standard lopinavir/ritonavir dosing have reported that 12%-16% were not fully suppressed at delivery.10-13 The study with the lowest HIV RNA detection rate, 50 copies per milliliter, reported 15.4% of women with detectable viral load at delivery.10
Until more is known about the relationship between lopinavir plasma concentrations and virologic response, a reasonable goal of lopinavir therapy during pregnancy is to achieve plasma unbound concentrations in pregnant women equivalent to those seen in nonpregnant adults. Although unbound concentrations increase by approximately 15% in late pregnancy, total lopinavir and ritonavir exposure during pregnancy are reduced by more than 50% likely due to a combination of increased clearance and decreased absorption. These physiologic factors may be addressed by increasing the administered dose of lopinavir/ritonavir. This goal is likely to be especially important in antiretroviral-experienced subjects, where the development of resistance has been associated with lower lopinavir concentrations.22-24 A recent population pharmacokinetic analysis of soft-gel capsule trough concentrations during pregnancy from a French cohort reported the likelihood of achieving various trough concentration targets with simulated standard versus increased (600/150 mg) tablet doses twice daily.25 The probability of achieving a trough concentration of >1 mg/L (used for treatment-naive patients) with the standard dose in this cohort was 96%. The probability of achieving a trough concentration of >4 mg/L or >5.7 mg/L (suggested targets for treatment-experienced patients) with standard doses fell to 50 and 21%, respectively. The increased dose of 600/150 mg twice daily had a 99%, 80%, and 53% probability of achieving >1, >4, and >5.7 mg/L, respectively. These authors suggested standard doses for treatment-naive patients and empirically increased doses and/or therapeutic drug monitoring during pregnancy for all others. A recent concentration-controlled study of intensive lopinavir tablet pharmacokinetics in 10 women during the second and third trimesters of pregnancy showed that lopinavir exposure was significantly lower in the second trimester compared with historical nonpregnant controls.26 Eight of 10 women required dose increases in the second trimester and achieved lopinavir exposure on the increased dose in the third trimester similar to nonpregnant historical controls. These findings are consistent with our findings.
Since this study was performed in US women, extrapolation to other populations may be confounded by differences in size, genetics, diet, and concomitant illnesses and other factors. Another limitation is that the pharmacokinetic evaluations within the first month postpartum may not reflect lopinavir/ritonavir pharmacokinetics in the nonpregnant/nonpostpartum female. Likewise, the changes in lopinavir/ritonavir pharmacokinetics during pregnancy are probably a continuous and dynamic process that cannot be fully characterized by only 2 evaluation time points during pregnancy. Despite these limitations, this study provides important information about lopinavir/ritonavir exposure to guide therapy during pregnancy.
Our current study evaluated complete 12-hour pharmacokinetic profiles with an empiric dose increase during pregnancy in all subjects, regardless of prior treatment status. A dose of 3 tablets (lopinavir 600 mg/ritonavir 150 mg) twice daily during the third trimester showed comparable exposure and tolerability to the standard dose (lopinavir 400 mg/ritonavir 100 mg twice daily) in nonpregnant adults. These data suggest that the higher lopinavir/ritonavir dose should be used in second and third trimester pregnant women, especially those who are protease inhibitor experienced, and that postpartum lopinavir/ritonavir dosing can be reduced to standard dosing before 2 weeks after delivery.
We thank the subjects who enrolled in this trial.
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APPENDIX I: MEMBERS OF THE IMPAACT 1026S PROTOCOL TEAM
In addition to the authors, members of the IMPAACT 1026s protocol team include: Francesca Aweeka, Pharm.D; Emily Barr, CPNP, CNM, MSN; Michael Basar, BA; Kenneth D. Braun, Jr, BA; Jennifer Bryant; Elizabeth Hawkins, BA; Kathleen A. Medvik, BS, MT; and Beth Sheeran, MS, RD.
Study Teams at Enrolling Sites: Los Angeles County + University of Southern California Medical Center: Francoise Kramer, MD; LaShonda Spencer, MD; James Homans, MD; and Andrea Kovacs, MD.
University of California San Diego Maternal, Child, and Adolescent HIV CRS: Andrew Hull, MD; Mary Caffery, RN; Jeanne Manning, RN; and Stephen A. Spector, MD.
Universities of Medicine And Dentistry of New Jersey, New Jersey Medical School: Arlene Bardeguez MD, MPH; Charmane Calilap-Bernardo RN; Linda Bettica RN; and Julliette Johnson RN.
Cook County Medical Center: Helen Cetjin, MD; Julie Schmidt, MD; Maureen Haak, RN MSN; and James McAuley, MD.
University of Colorado Denver: Emily Barr, PNP; Jill Davies, MD; Suzanne Paul, FNP; and Carol Salbenblatt, MSN.
Texas Children's Hospital: Shelly Buschur, RN, CNM; Chivon McMullen-Jackson, RN, BSN; Mary E. Paul, MD; and William T. Shearer, MD, PhD.
Columbia IMPAACT CRS: Sree Gaddipati, MD; Marc Foca, MD; Seydi Vazquez, MSN; and Alice Higgins, RN, MPA.
University of Miami Pediatrics Perinatal HIV/AIDS CRS: Amanda Cotter, MD; Liset Taybo, MD; Patricia Bryan, RN; and Erika Lopez, MD.
Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
HIV; lopinavir; mother-to-child transmission; pharmacokinetics; pregnancy