Paediatric pharmacokinetic studies

12 June 2008. Related: Conference reports, Paediatric care, CROI 15 (Retrovirus) 2008.

Polly Clayden, HIV i-Base

Correct dosing of antiretrovirals in HIV-positive children is complicated due to age-dependent changes in pharmacokinetics (PK) and the scarcity of data.

There were a number of posters at CROI showing PK data of old and new antiretrovirals in children from different age groups, and settings and with varying treatment experience.

Lopinavir/ritonavir in young infants

Data from the CHER study demonstrated a 76% reduction in early mortality in very young infants starting antiretroviral therapy (ART), regardless of clinical status, CD4 percentage or viral load. [1]

Since this finding, US guidelines (and others are expected to follow) recommend initiation of ART as soon as possible after birth for all infants age <12 months. [2]

Infants started on LPV/r 300 mg/m2 before 6 weeks of age have low LPV exposure after two weeks of treatment. The clinical relevance of these low concentrations depends on how rapidly infants acquire therapeutic LPV exposure.

Edmund Capparelli and co-workers from the USA and Brazil evaluated longitudinal PK and response to treatment in young infants initiated on LPV/r-containing regimens.

This was a prospective, phase I/II, open-label, dose-finding study using a dose of 300/75 mg/m2 twice daily + 2 NRTI in young infants >/=2 and <6 weeks of age.

Infants had a 12-hour PK evaluation after 2 weeks of treatment and a second PK evaluation at approximately 1 year of age. Trough LPV concentrations and viral load were assessed regularly during the first year of treatment.

Doses were modified to maintain LPV pre-dose (C-pre) >1 µg/mL and AUC <170 ug.hr/mL based on week-2 pharmacokinetic results.

10 infants were enrolled in the study before 6 weeks of age (median 5.6 weeks) with median viral load of 5.9 log copies/mL. Of these, 9 infants had evaluable PK at 2 weeks and 7 had repeat evaluations at 1 year of age.

The investigators reported that during the first year of treatment the overall median LPV C-pre was 2.3 µg/mL; 20% of levels were sub-therapeutic (<1 µg/mL). In individual infants, C-pre <1 was observed in 0% to 50% of levels. 9/10 and 7/10 infants had viral loads <1000 copies/mL at 16 weeks and 48 weeks, respectively.

Table1: LPV exposure increase during the first year of life

They found that infants with viral blips >1000 copies/mL between 8 wand 48 weeks were more likely to have sub-therapeutic C-pre, (r= 0.73, p= 0.016).

The investigators concluded that LPV/r exposure is initially low in infants <6 weeks of age but increases dramatically during the first year of life. But despite the low initial LPV exposure, most infants achieved viral load <400 copies/mL at 48 weeks.

They noted that viral loads >1000 copies/mL at 8 weeks and later, seen more frequently in infants with intermittently low LPV concentrations, suggested a link with difficulties in drug administration or adherence.

Recommended dose of lopinavir/ritonavir too low in protease inhibitor-experienced children

Lopinavir/r is approved for paediatric use in children aged 6 months and older at a dose of 230 mg/m2 twice daily, with a maximum of 400 mg/dose.

In adult PI-experienced patients, a target trough LPV concentration of <5.7 mg/L is associated with less likelihood of an undetectable viral load.

Natella Rahmanina and coworkers from the US reported findings from a study using modelling to determine whether this target is relevant in children, and can be achieved at the current recommended paediatric dose. [3]

Over 52 weeks, the investigators evaluated 50 PI-experienced children (4 to 17 years) receiving LPV/r-based therapy (single PI). Baseline resistance tests and 12-hour PK evaluations were performed (at second visit); viral load and adherence were assessed throughout the study.

Using multiple logistic regression, trough LPV concentration, adherence, and resistance were modelled as predictors of virologic outcome. PK data were fitted to candidate PK models. The model with the highest log-likelihood was used to simulate 5000 children to find the percentage with trough LPV concentration <5.7 mg/L after standard dosing.

The investigators found LPV resistance at baseline (p=0.003) and trough concentrations <5.7 (p=0.03) were significant predictors of never achieving viral load <400 copies/mL during the study period. In this model adherence did not predict virological outcome. LPV trough was <5.7 in 40% of the 5000 children simulations from this model.

The investigators wrote: “In this validated paediatric population pharmacokinetic model of LPV/r, the currently recommended dose of LPV will fail to consistently achieve this target in a large percentage of children. Further studies on therapeutic drug monitoring of LPV/r in children are warranted.”

Therapeutic drug monitoring of lopinavir and saquinavir in Thai children

Torsak Bunupuradah and coworkers from Thailand and the Netherlands looked at drug levels of PIs in a group of 50 Thai children. [4]

This was a prospective, open-label single-arm study of children receiving LPV/r and saquinavir (SQV) at standard doses.

Pre-dose plasma concentrations (Cmin) were taken at weeks 12, 24, 36, 48, 60, 72, 84, and 96. Children with Cmin <0.1 mg/L for LPV or 0.02 mg/L for SQV were excluded from the analysis because of suspected nonadherence.

Doses were adjusted according to clinical, growth, and Cmin. Cmin above the 50% inhibitory concentration (IC50) of >1.0 mg/L for LPV and >0.28 mg/L for SQV were targetted.

The children in this study had a median age at baseline of 9.3 years (IQR 7.1 to 11.2). For each time-point, 42 to 48 samples were available for analysis (348 for LPV and 353 for SQV).

The investigators found the overall mean (SD) of the Cmin were 5.52 (3.85) and 1.37 (1.24) mg/L for LPV and SQV, respectively. They reported no significant change over time for the Cmin levels.

At week 96, 5.5% and 3.7% had Cmin >IC50 for LPV and SQV respectively. The average dose for SQV decreased from 43 mg/kg at baseline to 34 mg/kg at week 96. The LPV dose remained almost the same: 228 mg/m2 and 229 mg/m2, at the same time-points.

The median intravariability over 96 weeks was 55% (IQR 41 to 76) and 67% (IQR 54 to 85) for LPV and SQV, respectively. The median intervariability was 69% (IQR 60 to 74) for LPV and 81% (IQR 76 to 94) for SQV.

The investigators noted that despite the dose reduction of 32% from standard dosing for SQV at week 96, the plasma levels indicate that further dose reduction is possible and that the high LPV Cmin suggests that dose reduction is reasonable. “Further research is warranted to establish a more appropriate dose for this Asian population”, they wrote.

Nevirapine exposure with WHO paediatric weight band dosing

Nevirapine (NVP) is dosed according to body surface area (150 to 200 mg/m2) or weight and age (7 mg/kg <8 years and 4 mg/kg >/=8 years). These dosing guidelines are far too complex for implementation in resource- limited settings and are themselves inconsistant. World Health Organisation (WHO) has developed a simple weight-band tables based on body surface area calculations of appropriate dose of key antiretroviral drugs for use in these settings. To date dosing of NVP(or other drugs) in this way has not been validated.

Edmund Capparelli and coworkers presented combined data from several paediatric trials of nevirapine PK and NVP exposure. PK values were modeled and comparisons made between values expected from dosing according to WHO guidelines to Food and Drug Administration (FDA) approved method (per kg). [5]

NVP PK data from 5 Pediatric AIDS Clinical Trials Group (PACTG) studies conducted in the United States were combined with data from Zambia (CHAPAS) and Thailand (IMPAACT P1056). Data from 565 children were included.

The AUC and Cmin with WHO dosing using 50-mg or 60-mg NVP (as part of FDC baby tablets with 3TC and d4T ie NVP/3TC/d4T of 50/30/6mg or 60/30/6mg) were assessed from the ratio of doses (parameter x WHO Dose/Study Dose). The frequency of sub-therapeutic concentrations (Cmin <3 µg/mL or AUC <48 ug.h/mL) and supra-therapeutic concentrations, 120 ug.h/mL (2x average) were determined.

The investigators performed a Monte Carlo simulation using a population PK model that included age, weight, ritonavir (RTV) use, and CYP 2B6 genotype. Using weight-band dosing, 7720 paediatric NVP concentration profiles were simulated.

The investigators found NVP AUC and Cmin were similar across the 3 countries (ie no difference in PK in the much more malnourished Zambian children). 94 children receiving RTV and 88 who were outside the WHO dosing weight groups (<5 or >30 kg) were excluded from the analysis.

The median, Cmin and AUC were 174 mg/m2 (IQR 162 to 187), 5.7 µg/mL (IQR 3.8 to 8.0), and 77.7 ug.h/mL (IQR 55.8 to 107.2) for WHO weightband dosing using 50/30/6mg ratios (based on the principal that NVP doses never go below 300mg/m2 and 153 mg/m2 (IQR 112 to 172), 4.6 µg/mL (IQR 3.0 to 6.9), and 62.2 ug.h/mL (IQR 45.1 to 90.8) for FDA dosing (4 or 7mg/kg). WHO dosing exceeded Cmin and AUC targets in 85% and 84% of children. The FDA dose met these targets in only 75% and 72% of children. The frequency of AUC >120 was higher with WHO than FDA dosing (18% vs 10%).

Increasing the ratio of NVP in FDCs (from 50mg to 60 mg NVP to be combined with 30mg 3TC and 6mg d4T) reduced the frequency of sub-therapeutic levels by 5%, but increased supra-therapeutic levels (>120%) by 12%. Monte Carlo simulation exceeded target AUC and Cmin in 77% of simulated patients.

The investigators concluded:

• The recommended WHO weight band dosing of NVP will result in therapeutic concentrations in approximately 80% of children without incurring a high frequency of excessive NVP exposures.
• The WHO weight band dosing of NVP achieves target exposure in a greater portion of children than the FDA dose of 4-7 mg/kg.
• Monte Carlo simulations produced similar NVP exposure to observed results from multiple clinical trials and can be used to help to optimise dose recommendations.
• The 50mg NVP tablet strength (50/30/6mg of NVP/3TC/d4T in FDC tablets used according to WHO weightbands) maximises the therapeutic index compared to other potential tablet strengths (such as 60/30/6 mg).
• WHO weight band dosing should be adopted in resource limited settings.

Nevirapine PK in Thai children receiving either an adult or paediatric fixed-dose combination of d4T, 3TC, and NVP

HIV-positive Thai children freqently receive a divided adult fixed-dose combination of stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) (30/150/200 mg/tablet.

A new chewable fixed-dose combination tablet of d4T/3TC/NVP (7/30/50 mg/tablet) for children has recently been introduced by the Thailand Government Pharmaceutical Organisation (GPO). (These are is the same ratios as in the Zambian Chapas trial 6/30/50 mg).

Kulkanya Chokephaibulkit from Thailand and the United States looked at NVP PK in Thai children receiving either adult (GPOvir S30) or paediatric (GPOvir S7) fixed-dose combinations [6].

In this study, NVP concentration data from 44 children (age 8.6+/- 2.9 years and weight 24.3+/- 8.3 kg) was combined from two clinical trials. Results from 9 children enrolled in IMPAACT P1056, an ongoing PK study comparing GPOvir S7 with the standard liquid formulations, who had intensive PK sampling pre-dose, and 0.5, 1, 2, 4, 8, and 12 hours post-dose were combined with data from a separate study of 35 children who received GPOvir S30 and had PK sampling pre-dose, and 2, 6 hours post-dose.

The investigators used a 1-compartment model and population approach to analyse the data. They found median NVP clearance was 0.081 L/h/kg and volume of distribution 1.79 L/kg across both formulations.

Children receiving NVP GPOvirS30 showed a slower absorption rate (p<0.001), but had comparable bioavailability (p>0.20) to those receiving GPOvirS7. The average NVP AUC was 75.5+- 40.5 and 81.1+/- 34.7 ug.hr/mL for GPOvir S30 and GPOvir S7, respectively. Median pre-dose NVP concentrations were higher with GPOvirS30 compared to GPOvirS7, 6.0 µg/mL (3.4 to 24.0) vs 4.3 µg/mL (3.0 to 10.0), p=0.06. All children achieved a pre-dose NVP concentration above the recommend target of 3.0 µg/mL.

The investigators concluded: “NVP pharmacokinetic parameters in Thai children using fixed-dose combination tablets containing either NVP 200mg or 50mg were within the range observed in prior paediatric studies.” They observed no clinically significant differences in NVP concentrations between the two formulations.

PK of etravirine (ETR, TMC125) in HIV-positive children between 6 and 17 years of age

Thomas Kakuda and coworkers from Tibotec showed findings from a study to determine the weight-based dose of ETR that will achieve exposures in children comparable to those in adults. [8]

This study enrolled HIV-1-positive children between 6 and </=17 years of age on a stable (at least 2 consecutive viral loads <50 copies/mL) on a LPV/r –containing regimen. TMC125 4 mg/kg twice daily was added for 7 days followed by a morning dose, and 12-hour PK assessment on day 8. Both 25 and 100-mg tablets were used. The 25mg tablet is currently only available for research purposes.

TMC125 PK was assessed using non-compartmental analysis; Cmin and AUC12h were compared to PK parameters in adults receiving 200 mg twice daily on a LPV/r-containing regimen.

PK assays were available for 16/17 children.10 children were aged between 6 and <12 years, and 6 between >/=12 and </=17 years. The mean (SD) Cmax and Cmin in 16 children were 555.2 (514.6) ng/mL and 233.2 (237.9) ng/mL, respectively.

Mean (SD) AUC12h was evaluable in 15 children and was 4788 (4459) ng.h/mL.

The investigators reported, relative to adults, the least square means ratio for Cmin and AUC12h was 1.08 (90% CI: 0.69 to 1.69) and 1.11 (90% CI: 0.76- 0.62), respectively.

They found interpatient PK variability was greater in children than adults, primarily as a result of 1 outlier. When the outlier was removed range of exposures in children was similar to that in adults. Exposure was not associated with age or body surface area (BSA).

There were no serious adverse events. 12 children reported at least 1 adverse event, mostly grade 1 or 2; 2 children (12%) developed a rash on treatment (grade 1 and 2, respectively), both on day 8 and resolving after 5 to 6 days; the AUC12h in these children were 7408 and 1826 ng.h/mL, respectively.

The investigators concluded:

• ETR at 4mg/kg bid following a meal provides comparative exposure in children age 6-17 to 200mg bid in adults.
• ETR was generally safe and well tolerated. Two patients developed mild to moderate transient rash (with no apparent association with ETR AUC12h).

As antiretrovirals are frequently under-dosed in children (in part because of increased variability), stage II of this trial with 30% higher dose 95.2mg/kg bid) is underway. A phase II trial to determine safety and efficacy in treatment-experienced children will begin after final dose selection.

References:

Unless otherwise stated, all references are from the 15th CROI, February 2008. Boston, MA, USA.

1. Violari A, Cotton M, Gibb D et al. Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young HIV-infected infants: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. Abstract WESS103.
2. Guidelines for the use of antiretroviral agents in pediatric HIV infection. February 28, 2008
3. Capparelli E, Pinto J, Robbins B et al. Lopinavir pharmacokinetic maturational changes and variability in HIV-infected infants beginning Kaletra therapy at <6 weeks of age. Poster abstract 573.
4. Rakhmanina N, Van Den Anker J,Van Guilder M et al. Recommended dose of lopinavir/ritonavir is sub-optimal in protease inhibitor-experienced children. Poster abstract 574.
5. van der Lugt J, Bunupuradah T, Kosalaraska P et al.Therapeutic drug monitoring of lopinavir and saquinavir in Thai HIV-infected children. Poster abstract 575.
6. Capparelli E, D Kabamba D, T Cressey T et al. Nevirapine exposure with WHO paediatric weight band dosing–enhanced therapeutic concentrations predicted based on extensive international pharmacokinetic experience. Poster abstract 576.
7. Chokephaibulkit K, Cressey T, W Prasitsuebsai W et al. Nevirapine pharmacokinetics in Thai children receiving either an adult or paediatric fixed-dose combination of stavudine, lamivudine, and nevirapine. Poster abstract 577.
8. Kakuda K, Konigs C, Feiterna-Sperling C et al. Pharmacokinetics of the next-generation NNRTI TMC125 in HIV-infected children between 6 and 17 years of age. Poster abstract 578.