Children who switched from twice- to once-daily lopinavir/ritonavir plus efavirenz had a low lopinavir trough concentration in a small Thai study.1 Troughs were not as low during twice-daily lopinavir/ritonavir dosing with or without efavirenz or with once-daily lopinavir/ritonavir without efavirenz. All children maintained an undetectable viral load, and those with low troughs had a dose increase.
In the United States once-daily lopinavir/ritonavir is licensed for antiretroviral-naive adults and for adults with fewer than three lopinavir-related resistance mutations. But data are sparse on the once-daily lopinavir/ritonavir tablet for children. To fill that pharmacokinetic gap, researchers in Thailand mounted a pilot study involving children already taking twice-daily lopinavir/ritonavir with or without the nonnucleoside efavirenz.
The 12 study participants had maintained a viral load below 40 copies for at least 3 months with twice-daily lopinavir/ritonavir. When children enrolled in the pilot trial, researchers collected blood samples over 12 hours to measure lopinavir levels. Then all children switched to an equivalent dose of once-daily lopinavir/ritonavir. Two weeks after the switch, the investigators collected blood samples over 24 hours.
Children combining lopinavir/ritonavir with two nucleosides and without efavirenz took lopinavir doses ranging from 255 to 283 mg/m2 (median 271) with twice-daily dosing and from 514 to 570 mg/m(2) (median 544) with once-daily dosing. These children had the following areas under the concentration-time curve (AUC), maximum concentrations (Cmax), and trough concentrations (C12h or C24h) before and after switching to once-daily lopinavir/ritonavir. See Table 1.
Children combining lopinavir/ritonavir with efavirenz took lopinavir doses ranging from 273 to 338 mg/m(2) (median 303) with twice-daily dosing and from 538 to 645 mg/m(2) (median 612) with once-daily dosing. They had the following lopinavir concentrations before and after switching to once-daily lopinavir/ritonavir. See Table 1.
Table 1: Median (Range) of Lopinavir PK Parameters, With and Without Efavirenz
|LPV/r without efavirenz (N=6)||LPV/r with efavirenz (N=5)|
|12-hour AUC twice daily (mcg x h/mL)||172 (125 to 201)||168 (124 to 190)|
|24-hour AUC once daily (mcg.hr/mL)||200 (95 to 228) *||154 (145 to 182) *|
|Cmax twice daily (mcg/mL)||8.8 (7.4 to 9.8)||10.3 (9.5 to 12.9)|
|Cmax once daily (mcg/mL)||12.1 (8.5 to 15.0)||13.5 (11.4 to 15.6) *|
|C12h twice daily (mcg/mL)||4.2 (2.0 to 6.5)||3.1 (1.2 to 3.4)|
|C12h once daily (mcg/mL)||3.9 (0.2 to 7.3)||0.17 (0.08 to 0.43) *|
For all 11 children who completed the study, the geometric mean ratio of lopinavir AUC once daily/twice daily was 1.01 (90% confidence interval 0.85 to 1.21). For Cmin, the geometric mean ratio of lopinavir once daily/twice daily was 0.21 (90% confidence interval 0.09 to 0.48). When taking lopinavir/ritonavir twice daily, all children had a lopinavir 12-hour (trough) concentration above 1 mcg/mL. After the switch to once-daily dosing, 5 of 6 children taking lopinavir without efavirenz and 0 of 6 taking lopinavir with efavirenz had a trough above 1.0 mcg/mL. The 7 children with a 24-hour lopinavir concentration below that cutoff after the switch to once-daily dosing had their dose increased by 20% to 30% after 12 weeks. Troughs remained low in 4 of these 7 children after the dose increase.
With once-daily lopinavir/ritonavir, median efavirenz concentrations were 62.6 (range 36.2 to 197.2) mcg x hr/mL for AUC, 4.1 (range 3.1 to 10.8) mcg/mL for Cmax, and 1.7 (range 0.9 to 6.0) mcg/mL) for Cmin.
All children maintained a viral load below 40 copies/mL through 24 weeks of once-daily lopinavir/ritonavir. No lopinavir/ritonavir side effects emerged, as might be expected in a group already tolerating twice-daily lopinavir/ritonavir well.
Several published studies have addressed lopinavir/ritonavir pharmacokinetics with once-daily dosing2-4 or with twice-daily dosing with efavirenz.5-7 In Canada a study of 7 children with a median age of 9.8 years found similar pharmacokinetics with once- and twice-daily dosing and no observable difference in tolerability.2 A Netherlands study of 19 children with a median age of 4.5 found evidence that a lopinavir/ritonavir dose of 460/115 mg/m(2) "leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children".3 Another Dutch study of 15 children with a median age 11.8 years found that a lopinavir/ritonavir dose of 300/75 mg/m(2) twice daily compensates for the enzyme-inducing effect of efavirenz given at 14 mg/kg once daily.
Mark Mascolini is with NATAP.org.
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