Reports of life-threatening cardiac, metabolic, renal and CNS dysfunction in newborns receiving lopinavir/ritonavir (LPV/r) in the first weeks of life have led to a recommendation that LPV/r should not be used in newborns <2 weeks postnatal and <42 weeks postconceptional age. Due to limited treatment options, however, clinicians may initiate LPV/r in newborns if benefit outweighs risk. Data on pharmacokinetics (PK) and safety of LPV/r in newborns are few.
IMPAACT P1106 is a multi-arm Phase IV study of PK/safety in newborns on antiretroviral and antituberculosis medicines received for clinical care at two South African sites. HIV-infected newborns in whom LPV/r was initiated at 1 μg/mL. Safety evaluations included echocardiograms (ECHOs) at baseline and weeks 1 and 6, and electrocardiograms at baseline, day 5, and weeks 1, 2, and 6. Adverse events (AE) were classified as expected (associated with prematurity) or unexpected.
Twenty-five newborns were enrolled;13 (52%) male and 22 (88%) black African. The median (interquartile range (IQR)) birth weight and gestational age were 2130 (1775, 2630) grams and 35 (32, 37) weeks, respectively. The median (IQR) age at enrollment was 45 (35, 61) days old. As of August 2017, 22 newborns contributed to 124 LPV concentrations. Median C0 was 4.7 (IQR 1.5, 7.4) µg/mL, with 1.5 and 4 hour levels approximately 1.5-2 times higher, similar to adults. LPV C0 was above target in 41/50 samples (figure 1). Of the 24 newborns with safety data, 11 had Grade 3/4 unexpected AEs (none treatment related) and four newborns had Grade 3/4 expected AEs. Most AEs were infection related (n=11). One infant died from presumed sepsis on day 2 of LPV/r. Infant ECHOs were normal except for two with mild abnormalities. No abnormal PR or QTc interval prolongation was observed. Median serum osmolality post LPV/r initiation was 289 (IQR 287, 291) mOsm/kg.
No treatment related adverse events were observed in this study of LPV/r safety and PK in newborns and very young infants. LPV concentrations were similar to adult levels, with most C0 >1 μg/mL.