Lopinavir Troughs Lower in Children on Once-Daily Dose With Efavirenz

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.

Study group ages ranged from 9.3 to 17.7 years (median 13.1), weight from 26.8 to 50.3 kg (median 40.8), CD4 count from 456 to 1239 (median 699), and CD4 percent from 16% to 31% (median 23%). Five of six children taking lopinavir/ritonavir with efavirenz and six taking the protease inhibitors without efavirenz completed both pharmacokinetic evaluations. Among children not taking efavirenz with the PIs, five were taking tenofovir/lamivudine and one zidovudine/didanosine.

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) *

* P <0.05 for once vs twice daily concetrations within group (not between group)

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 dosing^2-4 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.

References

1. Chokephaibulkit K et al. Pharmacokinetics of lopinavir/r tablets administered once versus twice daily with/without efavirenz in antiretroviral treatment experienced children. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 13–15 April 2011, Miami. Abstract P_19.
2. la Porte C et al. Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir treatment in HIV-1-infected children. Antivir Ther. 2009;14:603-606.
3. van der Lee M et al. Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2006;11:439-445
4. Rosso R et al. Lopinavir/ritonavir exposure in treatment-naive HIV-infected children following twice or once daily administration. J Antimicrob Chemother. 2006;57:1168-1171.
5. King JR et al. Steady-state pharmacokinetics of lopinavir/ritonavir in combination with efavirenz in human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 2009;28:159-161.
6. Bergshoeff AS et al. Increased dose of lopinavir/ritonavir compensates for efavirenz-induced drug-drug interaction in HIV-1-infected children. J Acquir Immune Defic Syndr. 2005;39:63-68.
7. Fraaij PL et al. Safety and efficacy of a NRTI-sparing HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2004;9:297-299.

Mark Mascolini is with NATAP.org.