(Last updated: March 28, 2014; last reviewed: March 28, 2014)
LPV/r is classified as Food and Drug Administration 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 ritonavir-boosted lopinavir (LPV/r) combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increased incidence of benign hepatocellular adenomas and increased combined incidence of hepatocellular adenomas plus carcinoma in male and female mice and male rats at doses that produced approximately 1.6 to 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 LPV/r did not cause a statistically significant increase in incidence of any other benign or malignant neoplasm in mice or rats.1
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.1
No evidence exists of teratogenicity with administration of LPV/r 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 (e.g., 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 perinatal 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.1
In the Antiretroviral Pregnancy Registry (APR), sufficient numbers of first-trimester exposures to LPV/r have been monitored for detection of at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with LPV/r. Among cases of first-trimester exposure to LPV/r reported to the APR, the prevalence of birth defects was 2.4% (23 of 969; 95% CI, 1.5% to 3.5%) compared with a total prevalence of 2.7% in the U.S. population, based on CDC surveillance.2
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. In contrast, in a study of plasma and hair drug concentration in 51 mother-infant pairs in Uganda receiving LPV/r during pregnancy and breastfeeding, infant plasma levels at delivery and hair levels at age 12 weeks suggested significant in utero transfer: 41% of infants had detectable plasma lopinavir concentrations at birth and mean infant to maternal hair concentrations at 12 weeks postpartum were 0.87 for lopinavir.3 However, transfer during breastfeeding was not observed, and no infant had detectable plasma lopinavir levels at 12 weeks. Lopinavir concentrations in human breast milk are very low to undetectable and lopinavir concentrations in breastfeeding infants whose mothers received lopinavir are not clinically significant.4-6
Human Studies in Pregnancy
The original capsule formulation of LPV/r has been replaced by a new tablet formulation that is heat-stable, has improved bioavailability characteristics, and does not have to be administered with food.7,8 Pharmacokinetic studies of standard adult LPV/r doses (400 mg/100 mg twice a day) using either the capsule or tablet formulations in pregnant women have demonstrated a reduction in lopinavir plasma concentrations during pregnancy of around 30% compared with that in non-pregnant adults.9-11 Increasing dose of LPV/r during pregnancy to 600 mg/150 mg (tablets) results in lopinavir plasma concentrations equivalent to those seen in non-pregnant adults receiving standard doses.12,13 Reports of clinical experience suggest that most, but not all, pregnant women receiving standard LPV/r tablet dosing during pregnancy will have trough lopinavir concentrations that exceed 1.0 mcg/mL, the usual trough concentration target used in therapeutic drug monitoring programs for antiretroviral-naive subjects, but not the higher trough concentrations recommended for protease inhibitor-experienced subjects.7,10 Lopinavir plasma protein binding is reduced during pregnancy, but the resulting increase in free (unbound) drug is insufficient to make up for the reduction in total plasma lopinavir concentration associated with pregnancy.14,15
These PK studies suggest that LPV/r doses should be increased to 600 mg/150 mg twice a day in all HIV-infected pregnant women during the second and third trimesters. If standard doses of LPV/r are used during pregnancy, virologic response and lopinavir drug concentrations, if available, should be monitored. An alternative strategy for increasing exposure to LPV/r during pregnancy is to add a pediatric LPV/r tablet (100/25 mg) to the standard dose of two adult 200/50 mg tablets.15 Once-daily dosing of LPV/r is not recommended in pregnancy because no data exist to address whether drug levels are adequate with such administration.
LPV/r oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/volume) propylene glycol. Reduced hepatic metabolic and kidney excretory function in newborns can lead to accumulation of lopinavir as well as alcohol and propylene glycol, resulting in adverse events such as serious cardiac, renal, metabolic, or respiratory problems. Preterm babies may be at increased risk because their metabolism and elimination of lopinavir, propylene glycol, and alcohol are further reduced. Post-marketing surveillance has identified 10 neonates (i.e., babies aged <4 weeks), nine of whom were born prematurely, who received LPV/r and experienced life-threatening events.16 In a separate report comparing 50 HIV-exposed newborns treated with LPV/r after birth to 108 HIV-exposed neonates treated with zidovudine alone, elevated concentrations of 17-hydoxyprogesterone and dehydroepiandrosterone-sulfate, consistent with impairment of 21α-hydroxylase activity, were seen only in the lopinavir-exposed infants. All term infants were asymptomatic but three of eight preterm infants had life-threatening symptoms, including hyponatremia, hyperkalemia, and cardiogenic shock, consistent with adrenal insufficiency.17 LPV/r 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.