Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Protease Inhibitors
Lopinavir + Ritonavir (Kaletra, LPV/r)
(Last updated:9/14/2011)
Lopinavir + Ritonavir (Kaletra, LPV/r) is classified as FDA pregnancy category C.
Animal carcinogenicity studies
Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays. The lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in male and female mice and male rats at doses that produced approximately 1.6–2.2 times (mice) and 0.5 times (rats) the human exposure at the recommended therapeutic dose of 400 mg/100 mg (based on AUC0–24hr measurement). Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.
Reproduction/fertility
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats with exposures approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose.
Teratogenicity/developmental toxicity
No evidence exists of teratogenicity with administration of lopinavir/ritonavir to pregnant rats or rabbits. In rats treated with a maternally toxic dosage (100 mg lopinavir/50 mg ritonavir/kg/day), embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations, and skeletal ossification delays) were observed. Drug exposure in the pregnant rats was 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose. In a peri- and postnatal study in rats, a decrease in survival of pups between birth and postnatal Day 21 occurred with exposure to 40 mg lopinavir/20 mg ritonavir/kg/day or greater. In rabbits, no embryonic or fetal developmental toxicities were observed with a maternally toxic dosage, where drug exposure was 0.6-fold for lopinavir and 1-fold for ritonavir of the exposures in humans at the recommended therapeutic dose.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to lopinavir/ritonavir have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with lopinavir/ritonavir. Among cases of first-trimester lopinavir/ritonavir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.2% (16 of 738 births, 95% CI, 1.2%–3.5%) compared with a total prevalence of 2.7% in the U.S. population, based on CDC surveillance [1].
Placental and breast milk passage
Lopinavir crosses the human placenta; in the P1026s PK study, the average ratio of lopinavir concentration in cord blood to maternal plasma at delivery was 0.20 ± 0.13. For ritonavir, data in humans indicate only minimal transplacental passage (see ritonavir). Lopinavir and ritonavir are secreted in the breast milk of lactating rats; it is not known if either drug is excreted in human milk.
Human studies in pregnancy
The capsule formulation of lopinavir/ritonavir is no longer available; it has been replaced by a new tablet formulation of lopinavir 200 mg/ritonavir 50 mg that is heat stable and does not have a food requirement.
In nonpregnant adults, plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg lopinavir/ritonavir tablets are similar to those achieved with three 133/33 mg lopinavir/ritonavir capsules given with food, although with less PK variability. In a study of 51 pregnant women, plasma trough lopinavir levels during the third trimester were compared among 28 women receiving the capsule and 23 women receiving the tablet formulations at standard dosing. No statistical difference was found between the groups, with a mean lopinavir trough level of 4.86 mg/L (capsule) and 4.57 mg/L (tablets) [2]. However, the inter-individual variability was lower with the tablets than with the capsules. Five of 28 women (17.8%) in the capsule group and 4 of 23 women (17.4%) in the tablet group had trough levels less than the target (3 mg/L); 7 of the 9 women had HIV RNA levels less than detection at the time of their sampling, and 2 with subtherapuetic levels (0.7 and 2.44 mg/L) had plasma RNA of 83 and 56 copies/mL, respectively, at the time of their sampling.
P1026s evaluated lopinavir PKs following standard dosing with the new lopinavir/ritonavir tablet formulation (2 tablets twice daily) until 30 weeks’ gestation, followed by an increase to 3 tablets twice daily and return to standard dosing at postpartum hospital discharge. Median AUC was 72 µg*h/mL in 7 women receiving standard dosing during the second trimester, 97 µg*h/mL in 25 women receiving the increased dose during the third trimester, and 129 µg*h/mL in 19 women receiving standard dosing at 2 weeks postpartum. These data suggest that the higher lopinavir/ritonavir dose should be used in the third trimester; that it should be considered in the second trimester, particularly in women who are PI experienced; and that lopinavir/ritonavir can be reduced to standard dosing shortly after delivery [3]. An alternative strategy for increasing lopinavir/ritonavir exposure during pregnancy is to add a pediatric lopinavir/ritonavir tablet (100/25 mg) to the standard dose of 2 adult tablets (200/50 mg) [4].
Once-daily dosing of lopinavir/ritonavir capsules or tablets is not recommended in pregnancy because no data exist to address whether drug levels are adequate with such administration.
Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/volume) propylene glycol. Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation of lopinavir (the active ingredient) as well as alcohol and propylene glycol. Preterm babies may be at increased risk of health problems because they cannot metabolize propylene glycol; this could lead to accumulation and adverse events such as serious heart, kidney, or breathing problems. Postmarketing surveillance has identified 10 neonates (babies <4 weeks of age), 9 of whom were born prematurely, who received lopinavir/ritonavir and experienced life-threatening events [5]. Lopinavir/ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth, plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained.
References
1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2011. Wilmington, NC: Registry Coordinating Center; 2010. Available from URL: http://www.APRegistry.com. 2011.
2. Khuong-Josses MA, Azerad D, Boussairi A, Ekoukou D. Comparison of lopinavir level between the two formulations (soft-gel capsule and tablet) in HIV-infected pregnant women. HIV Clin Trials. 2007 Jul-Aug;8(4):254-255.
3. Best BM, Stek AM, Mirochnick M, et al. Lopinavir tablet pharmacokinetics with an increased dose during pregnancy. J Acquir Immune Defic Syndr. 2010 Aug 1;54(4):381-388.
4. Patterson KB, Dumond JB, Prince HA, et al. Pharmacokinetics of the lopinavir/ritonavir tablet in HIV-infected pregnant women: a longitudinal investigation of protein bound and unbound drug exposure with empiric dosage adjustment. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 27-Mar 3, 2011; Boston, MA.
5. Boxwell D, Cao K, Lewis L, Marcus K, Nikhar B. Neonatal toxicity of Kaletra oral solution: LPV, ethanol or prophylene glycol? Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); Feb. 27-Mar 3, 2011; Boston, MA.