Lopinavir/ritonavir oral solution toxicity in neonates

Polly Clayden, HIV i-Base

Lopinavir/ritonavir (LPV/r, Kaletra) oral solution is approved by the FDA for infants 14 days of age and older. US guidelines do not recommend its use in preterm infants.

LPV/r oral solution has particular pharmacokinetic properties that make its use complicated in neonates. It contains high volumes of both ethanol (356.3 mg/mL, 42% volume solute/volume solution (v/v) and propylene glycol (152.7 mg/mL, 15.3% v/v).

Neonates have reduced alcohol dehydrogenase and CYP3A4 activity and immature renal function. Ethanol is 95% and propylene glycol is 55-75% metabolised in the liver by alcohol dehydrogenase. Ethanol inhibits the metabolism of propylene glycol by alcohol dehydrogenase leading to elevated concentrations. LPV is metabolised by CYP3A.

Reduced hepatic metabolism and renal clearance in neonates, particularly in preterm infants, can lead to accumulation of all three ingredients to toxic levels.

Acute ethanol toxicity is linked to central nervous system (CNS) and respiratory depression, and gastritis. Propylene glycol is also associated with CNS and respiratory depression, as well as renal failure and metabolic acidosis. LPV has been shown to cause PR and QT interval prolongation and AV block in adults with very high levels of the drug.

Cases of toxicity in neonates – particularly preterm – have been reported to the FDA Adverse Event Reporting System (AERS).

A poster authored by Debra Boxwell and colleagues from the FDA showed data from case studies from a search of the AERS database for all reports of toxicity in children 2 years of age or under following dosing with LPV/r oral solution.

The search revealed 10 unduplicated cases in neonates of whom 8 were preterm. Of the preterm infants, 3 were born at 28 weeks gestation, 1 at 30 weeks, 2 at 32 weeks and 2 at 34 weeks.

The documented adverse events included cardiac toxicity (bradycardia, complete AV block, bundle branch block, or cardiac failure; (n=7), acute renal failure (n=5), increased serum creatinine (n=1), elevated serum lactate level (n=2), hyperkalemia (n=4), respiratory failure (n=2), hypotonia (n=1), abnormal EEG (n=1), and CNS depression (n=1).

Outcomes included 1 death, 2 life threatening and 4 hospitalisations. Therapy was initiated on the day of birth in 7 neonates, day after birth in 1, day 34 in 1, and unknown in 1.

Onset the first adverse event occurred within 1 to 6 days (n = 8). Discontinuation of Kaletra (n=9) resulted in recovery within 1 day in 1, 2 days in 2, 3 days in 2, 6 days in 3, 20 days in 1 and was unknown in 1.

WHO set 25mg/kg as a maximum acceptable daily intake of propylene gel when it is used as a food additive. The European Medicines Agency (EMA) recommends that a 12.5mg/dL blood concentration of ethanol after a dose of any medication should not be exceeded. In IMPAACT P1030 – a PK sub-study in full-term infants 6 weeks of age – the mean steady state of LPV was 5.2+1.8ug/m2 twice daily. When the FDA investigators looked at neonatal exposure to the three ingredients in the cases for which data were available, the results were far in excess of these recommendations. See Table 1: Neonatal exposure to lopinavir, ethanol and propylene glycol.

Table 1: Neonatal exposure to lopinavir, ethanol and propylene glycol
Reported LPV/r dose Daily propylene glycol intake (mg/kg/day) Calculated blood ethanol concentration per dose (mg/dL)3 Highest measured LPV level (ug/mL)
230 mg/m2 BID 89.5 11.0
230mg/m2 BID 87.4 10.6
30mg TID 81.8 6.8 25.3
30mg TID 78.1 6.5 20.2
520mg QD 451.2 X 1 111 28.5
40mg BID 117.5 14.5 16.2
20mg/kg BID 76.4 11.3 29.2

The investigators concluded that the ten cases to the AERS suggest that neonates, especially those born preterm, who received LPV/r oral solution, were at increased risk of toxicities from drug accumulation. They added that the improvement of symptoms when the drug was stopped support this association.

There are limitations to the AERS however. Because reporting is voluntary, the quality of reporting is very variable. The database is subject to under reporting as well as reporting bias and both the numerator and the denominator are unknown for any event reviewed. Therefore the incidence or estimated risk cannot be calculated.


This analysis provoked a FDA label change and the lopinavir/r oral solution is not recommended for neonates particularly preterm.


Boxwell D et al. Neonatal toxicity of Kaletra oral solution— LPV, ethanol or propylene glycol. 18th CROI, 27 February– 2 March 2011, Boston. Poster abstract 708.

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