Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below.

BACKGROUND: Lopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children >6 months in the US and >2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2 twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective. METHODS: HIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cmin was <1.0 mg/l LPV/r dose was increased by 33%. Plasma trough levels were drawn subsequently. HIV-1 RNA was followed-up until week 48. RESULTS: A total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4-13.2) years. Mean (+/-SD) AUC0-12h, Cmax and Cmin of LPV were 75.3 (+/-33.7) mg/l.h, 9.33 (+/-3.27) mg/l and 3.68 (+/-2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cmin was inadequate in 7/23 children. Significantly more children <2 years had inadequate Cmin compared with children >2 years. Dose increase to +/-300/75 mg/m2 LPV/r led to Cmin >1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients. CONCLUSIONS: Mean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children <2 years. Prospective pharmacokinetic studies using 300/75 mg/m2 LPV/r in this age population are urgently warranted.

Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children.

OBJECTIVE: To assess the pharmacokinetics and 24-week efficacy and safety of dual boosted saquinavir/lopinavir/ritonavir combination in children. DESIGN: Twenty reverse transcription inhibitor-pretreated children at 2 centers in Thailand were treated with saquinavir/lopinavir/ritonavir in an open label, single arm, 6-month prospective study. The dosage was 50 mg/kg twice daily (bid) for saquinavir and 230/57.5 mg/m bid for lopinavir/ritonavir. Ten children also received lamivudine. METHODS: Samples were collected for a 12-hour pharmacokinetic profile in all children. Plasma concentrations of saquinavir, lopinavir and ritonavir were determined using a validated high performance liquid chromatography technique. RESULTS: At baseline, the median age was 8.5 years, with human immunodeficiency virus (HIV) RNA 4.9 log10 copies/mL, CD4 count 129 cells/microL and CD4%, 6.5%. Median area under the concentration curve at 0-12 hours and Cmin were 39.4 mg/L.h and 1.4 mg/L for saquinavir and 118 mg/L.hr and 5.9 mg/L for lopinavir. After 24 weeks of treatment, HIV RNA was suppressed below 400 copies/mL for 16 of 20 (80%) children (intent-to-treat analysis) and below 50 copies/mL for 12 of 20 children (60%), and CD4% (count) rose by a median of 6% (216 cells/microL). Median changes of triglyceride and total cholesterol were 56 and 36.5 mg/dL, respectively (P = 0.01). Lopinavir Cmin <1 and saquinavir Cmin <0.28 mg/L correlated with HIV RNA >400 copies/mL, and lopinavir Cmax >15 mg/L correlated with rises in cholesterol (P < 0.05). CONCLUSION: Plasma drug concentrations of saquinavir, lopinavir and ritonavir were at the higher limits of expected ranges for adult treatment at approved dosages (1000/100 mg bid for saquinavir, 400/100 mg bid for lopinavir/ritonavir). The regimen was well-tolerated and had good efficacy at 24 weeks. This dual boosted protease inhibitor combination should be assessed in larger trials of reverse transcription inhibitor-experienced children.

Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13).

BACKGROUND: There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children. METHODS: Children aged 2-13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0-24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response. RESULTS: 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1-12.8) years] had evaluable PK data for 3TC (n=19) and/or ABC (n=14). GMRs of 3TC and ABC AUC0-24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2-6 versus 6-13 years old (P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2-6 versus 6-13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24. CONCLUSION: AUC0-24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.

Increased dose of lopinavir/ritonavir compensates for efavirenz-induced drug-drug interaction in HIV-1-infected children.

BACKGROUND: Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied. OBJECTIVE: To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children. METHODS: Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data. RESULTS: Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children. CONCLUSION: The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

Plasma levels of zidovudine twice daily compared with three times daily in six HIV-1-infected children.

OBJECTIVES: Zidovudine is often administered every 12 h in HIV-infected children, but so far no pharmacokinetic data are available for the administration of this agent every 12 h. We have evaluated the plasma pharmacokinetics of zidovudine administered every 8 h versus every 12 h in HIV-1-infected children. METHODS: In HIV-1-infected children who switched from zidovudine every 8 h to every 12 h, a pharmacokinetic curve was recorded both before and after the switch. Zidovudine plasma levels were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS: Six HIV-1-infected children [median age (range) 7.8 (2.5-13.4) years] were included. In these patients, geometric mean ratios of AUC(0-24) and C(max) for zidovudine every 12 h versus every 8 h were not significantly different from 1.0. CONCLUSIONS: The plasma pharmacokinetic parameters of zidovudine taken every 8 h and every 12 h were not significantly different and therefore suggest bioequivalence of these two dose frequencies.

Nelfinavir plasma concentrations are low during pregnancy.

Plasma nelfinavir concentration ratios (CRs) were calculated for all pregnant (n=27) and nonpregnant (n=48) human immunodeficiency virus type 1-infected women receiving the drug who visited our outpatient clinic. In pregnant women, mean and median nelfinavir CRs were significantly lower (P=.02 and P=.04, respectively), and 51% of the CRs were below the clinically relevant threshold of 0.90, compared with 35% of the CRs in nonpregnant women. After we adjusted for confounders, we found that the mean nelfinavir CR was 34% lower in pregnant women (P=.02). With targeted interventions, subsequent CRs in pregnant women showed a significant increase (median increase, 0.31; P=.01).

Maintaining the nelfinavir trough concentration above 0.8 mg/L improves virologic response in HIV-1-infected children.

Differences in virologic response were compared in 32 HIV-infected children with a nelfinavir trough concentration either below (n=7) or above (n=25) 0.8 mg/L. Virologic response at week 48 was observed in 29% of children with subtherapeutic nelfinavir troughs versus 80% in children with therapeutic nelfinavir troughs (P=.02).

Safety and efficacy of a NRTI-sparing HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children.

We studied a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the treatment of children infected with NRTI-resistant HIV-1. The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years). Observed side effects were transient with the exception of dyslipidaemia.

Pharmacokinetics of nelfinavir in children: influencing factors and dose implications.

OBJECTIVES: The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels. METHODS: HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated. RESULTS: Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged < 2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8 < 12.5 mg/l x h [odds ratio (OR) (95% CI): 2.44 (0.41-14.7) and 8.7 (0.79-95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r = 0.89, P < 0.001). C8 > 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight. CONCLUSION: Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.

Ritonavir-enhanced pharmacokinetics of nelfinavir/M8 during rifampin use.

OBJECTIVE: To describe a case of successful protease inhibitor-based highly active antiretroviral therapy (HAART) concomitant with rifampin. CASE SUMMARY: In a 7-month-old male infant with tuberculosis and HIV-1 infection, tuberculosis therapy including rifampin and HAART containing the protease inhibitor nelfinavir 40 mg/kg every 8 hours was started. Intensive steady-state pharmacokinetic sampling from baseline to 8 hours revealed very low plasma concentrations of nelfinavir: area under the plasma concentration-time curve (AUC(0-24)) <10% of adult population values for 750 mg every 8 hours and nonquantifiable concentrations of nelfinavir's principal metabolite (M8). Nelfinavir 40 mg/kg every 8 hours was then substituted with nelfinavir 30 mg/kg twice daily plus ritonavir 400 mg/m(2) twice daily. Intensive steady-state (0-12 h) pharmacokinetic sampling was repeated. Nelfinavir concentrations had improved, but remained low when compared with adult population values of 1250 mg every 12 hours: AUC(0-24) 21.9 versus 47.6 mg/L*h (46%) and 12-hour trough level (C(12)) 0.25 versus 0.85 mg/L (29%). However, concentrations of M8 considerably exceeded population values: AUC(0-24) 57.5 versus 13.6 mg/L*h (443%) and C(12) 1.35 versus 0.28 mg/L (482%). Since M8 concentrations were highly elevated, pharmacokinetic parameters for (nelfinavir + M8) were used rather than those for nelfinavir alone. Thus, AUC(0-24) (nelfinavir + M8) and C(12) (nelfinavir + M8) comprised 130% and 142%, respectively of the adult population values. This, in addition to good clinical response and tolerability, favored continuation of the regimen. CONCLUSIONS: In an infant, nelfinavir-containing HAART was successfully used with rifampin after the addition of ritonavir. Ritonavir resolved the pharmacokinetic interaction between rifampin and nelfinavir by boosting nelfinavir and, especially, M8 concentrations. More research is needed to confirm these results.

Therapeutic drug monitoring of indinavir and nelfinavir to assess adherence to therapy in human immunodeficiency virus-infected children.

INTRODUCTION: Adherence to highly active antiretroviral therapy is required to obtain an optimal long term virologic response rate of HIV-1-infected children. Plasma concentrations of protease inhibitors (PIs) outside the limits of the reference values indicate nonadherence to antiretroviral therapy in adults. We studied during a 2-year follow-up period routinely taken plasma protease inhibitor concentrations to assess adherence to antiretroviral therapy in HIV-1-infected children. METHODS: In 40 children (ages 3 months to 18 years) blood samples were taken at regular outpatient visits every 12 weeks after the start of highly active antiretroviral therapy and analyzed for plasma concentrations of indinavir or nelfinavir by high performance liquid chromatography and for plasma HIV-1 RNA load. The percentage of samples fulfilling the criteria for adherence was assessed for each child by three methods. For each sample a concentration ratio was calculated by dividing the concentration in that sample by the time-adjusted population value. According to Method 1 concentration ratios below or above concentration ratio limits (CORALs) of population data obtained in adults were highly indicative of nonadherence. Because many children have high PI levels, Method 2 evaluated plasma samples of PIs with only the lower CORAL. According to Method 3 only children with plasma samples below the limit of quantification (0.04 mg/l) were considered noncompliant. Differences in adherence rate between virologic responders and virologic nonresponders and between adherence rates and the two protease inhibitors were analyzed. The cumulative incidence of HIV-1 RNA levels >500 copies/ml in children was calculated. RESULTS: Thirty-one children started treatment with indinavir, and nine children started treatment with nelfinavir. The median adherence rates for indinavir as determined by methods 1, 2 and 3 were 54% [interquartile range (IQR), 25 to 69%], 67% (IQR 50 to 92%) and 80% (IQR 63 to 100%), respectively. For nelfinavir median adherence rates of 60% (IQR 39 to 75%), 100% (IQR 67 to 100%) and 100% (IQR 100 to 100%) were observed. Adherence rates calculated with Method 2 were significantly higher in virologic responders ( = 0.04). Adherence rates calculated with Methods 2 and 3 were significantly lower in children using indinavir compared with those using nelfinavir ( = 0.02 and = 0.02, respectively). CONCLUSION: Calculation of adherence rates using the lower limit of CORALs of indinavir or nelfinavir in children may be a useful measurement for the assessment of nonadherence to antiretroviral therapy in children.