Skip Navigation LinksHome > February 20, 2012 - Volume 26 - Issue 4 > Pharmacokinetics and short-term safety and tolerability of e...
AIDS:
doi: 10.1097/QAD.0b013e32834f30b1
Clinical Science

Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents

Königs, Christopha; Feiterna-Sperling, Corneliab; Esposito, Susannac; Viscoli, Claudiod; Rosso, Raffaellad,*; Kakuda, Thomas N.e; Leemans, Ruudf; Peeters, Monikag; Mack, Rebeccae; Peeters, Ingeborgg; Sinha, Rekhag; Boven, Katiae; Giaquinto, Carloh

Free Access
Article Outline
Collapse Box

Author Information

aDepartment of Pediatrics and Adolescent Medicine, Johann Wolfgang Goethe-University, Frankfurt am Main

bDepartment of Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany

cDepartment of Maternal and Pediatric Sciences, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan

dSan Martino Hospital, University of Genoa, Genoa, Italy

eTibotec Inc., Titusville, New Jersey, USA

fJohnson & Johnson Pharmaceutical Research and Development

gTibotec BVBA, Beerse, Belgium

hDepartment of Pediatrics, University of Padua, Padua, Italy.

*Raffaella Rosso deceased.

Correspondence to Christoph Königs, MD, Department of Pediatrics and Adolescent Medicine, Johann Wolfgang Goethe-University Hospital, Hs 32, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany. Tel: +49 69 6301 83030; fax: +49 69 6301 83991; e-mail: ckoenigs@zki.uni-frankfurt.de

Received 14 July, 2011

Revised 11 November, 2011

Accepted 14 November, 2011

Data previously presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI): 3–6 February 2008, Boston, Massachusetts, USA (abstract 578) and the 16th CROI: 8–11 February 2009, Montreal, Canada (abstract 879).

Collapse Box

Abstract

Objectives: To evaluate the pharmacokinetics, weight-based dose selection and short-term safety and tolerability of etravirine in HIV-1-infected children and adolescents.

Design: Phase I, nonrandomized, open-label study in two stages.

Methods: Children and adolescents aged at least 6 years to 17 years or less on a stable lopinavir/ritonavir-based antiretroviral regimen with HIV-1 RNA plasma viral load less than 50 copies/ml were enrolled. In both stages, etravirine (4 mg/kg twice daily in stage I, 5.2 mg/kg twice daily in stage II), added to the existing antiretroviral regimen, was administered for 7 days followed by a morning dose and 12-h pharmacokinetic assessment on day 8. Pharmacokinetic parameters were determined using noncompartmental analysis. Data were compared with those previously established in HIV-1-infected adults on a similar etravirine (200 mg twice daily) combination antiretroviral regimen.

Results: Twenty-one patients were recruited to each stage; 19 and 20 had evaluable pharmacokinetics in stages I and II, respectively. Mean (SD) maximum plasma concentrations in stages I and II were 495 (453) and 757 ng/ml (680), respectively; area under the plasma concentration–time curve over 12 h was 4050 (3602) and 6141 ng h/ml (5586), respectively. Statistical/qualitative comparisons showed comparable exposures with adults in stage II; however, the upper 90% confidence interval fell outside the predefined range. Plasma viral load remained undetectable on day 8 in all patients, and etravirine was well tolerated at both doses.

Conclusion: Etravirine 5.2 mg/kg was well tolerated in this study and this dose was selected for further investigation in clinical trials.

Back to Top | Article Outline

Introduction

Although several antiretroviral drugs are approved for the treatment of HIV-1-infection in children who are naive to treatment, there remains a lack of options for treatment-experienced, HIV-1-infected children [1]. Guidelines for the second-line treatment of HIV-1 infection in children recommend the use of three fully active agents wherever possible. This usually consists of two nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] and either a boosted HIV protease inhibitor or a non-NRTI (NNRTI), depending on whether failure occurred after NNRTI-based or protease inhibitor-based therapy, respectively [2–5].

The NNRTI etravirine is approved in combination with other antiretroviral drugs for the treatment of HIV-1-infected, treatment-experienced adults. Two phase III, randomized, double-blind, placebo-controlled trials (DUET-1 and DUET-2) demonstrated the efficacy and safety of an etravirine-containing regimen in HIV-1-infected adults with documented resistance to first-line NNRTIs for up to 96 weeks [6–9]. There was no apparent relationship between the pharmacokinetics of etravirine and efficacy or safety in the DUET trials [10]. The antiviral activity and generally favorable safety profile of etravirine in HIV-1-infected adults suggests a potential to explore the use of this drug in treatment-experienced, HIV-1-infected children.

Although data with antiretroviral agents in treatment-experienced children are sparse, some clinical data are available and several clinical trials are currently in progress. Salazar et al. [11] showed that after 48 weeks of ritonavir-boosted tipranavir, approximately 35% of HIV-1-infected children and adolescents achieved HIV-1 RNA viral load less than 50 copies/ml, with an acceptable tolerability profile. Furthermore, with the boosted protease inhibitor darunavir, approximately 50% of treatment-experienced children and adolescents achieved HIV-1 RNA viral load less than 50 copies/ml after 48 weeks of treatment [12]. Other trials in treatment-experienced children and adolescents are currently underway, including with darunavir (dArunavir in tReatment experIenced pEdiatric population, ARIEL, NCT00919854); etravirine (Pediatric trial with Intelence as an Active NNRTI Option, PIANO, NCT00665847); maraviroc (NCT00791700); and raltegravir (International Maternal Pediatric Adolescent AIDS Clinical Trials P1066, NCT00485264).

Nonetheless, treatment of HIV-1-infected children who have failed prior treatment remains a difficult challenge. Drug resistance is common, particularly with the first-generation NNRTIs (efavirenz and nevirapine); reasons for failure were considered to be a low genetic barrier for developing resistance, underdosing, low drug levels and suboptimal adherence [13,14]. Indeed, dose optimization of antiretrovirals remains problematic, as children often require higher weight-based dosing of antiretroviral drugs than adults due to differences in drug absorption, body composition and metabolic activity [15]. Furthermore, the population of treatment-experienced children requiring second-line regimens is likely to increase with time, a particular challenge in resource-limited countries where the need for effective, affordable options will be acute.

The aim of this study was therefore to determine a weight-based dose of etravirine that achieves comparable pharmacokinetic exposures in HIV-infected children and adolescents aged at least 6 years to 17 years or less and weighing at least 20 kg as HIV-infected adults receiving 200 mg twice daily (b.i.d.). A secondary objective was to assess the short-term safety and tolerability of etravirine.

Back to Top | Article Outline

Participants and methods

The trial protocol and subsequent amendments were approved by Independent Ethics Committees and/or Institutional Review Boards. The study was conducted in accordance with the principles of Good Clinical Practice and the revised Declaration of Helsinki. Risks were minimized as much as possible given that participation in the study had no direct benefits for the participants [16]; however, it was not expected that the exposure to current antiretroviral drugs would change upon addition of etravirine. Children (≥6 to <12 years) agreed to participate in the study and their parent(s)/legal guardian(s) provided written consent prior to any study-related procedure. Adolescents (≥12 to ≤17 years) and their parent(s)/legal guardian(s) provided written consent prior to any study-related procedure.

Back to Top | Article Outline
Participants

Treatment-experienced, HIV-1-infected children and adolescents between the ages of 6 and 17 years inclusive, weighing at least 20 kg, but below the 90th percentile for weight [17] were recruited. Participants were required to be on a stable regimen of at least two NRTIs and lopinavir/ritonavir, with or without enfuvirtide (at approved pediatric doses) for at least 2 months, with a HIV-1 RNA viral load less than 50 copies/ml on two consecutive determinations, and were not expected to change their regimen in the next 15 days.

Main exclusion criteria were a life expectancy of less than 6 months (as assessed by the investigator), a currently active AIDS-defining illness, hepatitis A, B or C infection at screening and any grade 3 or 4 toxicity [18]. The use of investigational drugs (except tenofovir disoproxil fumarate, which was allowed) was prohibited from 30 days prior to the first intake of study medication until the last follow-up visit. Study discontinuation was mandatory in the event of any grade 3 or 4 adverse event, at least grade 2 rash (but not after the last dose of etravirine in the case of grade 2 rash), clinical hepatitis or persisting grade 2 nausea at least, pregnancy or at the investigator's discretion.

Back to Top | Article Outline
Study design and treatment

This was a phase I, open-label, nonrandomized trial in which etravirine was administered for 8 days in addition to the existing antiretroviral therapy including lopinavir/ritonavir. The trial was structured in two sequential stages (stages I and II), each with a 28-day screening period and a 1-month, posttreatment, follow-up period. For each stage, 20 patients were to be enrolled; 10 into each cohort (children aged ≥6 to <12 years and adolescents aged ≥12 to ≤17 years). The first 20 patients were enrolled in stage I (etravirine 4 mg/kg b.i.d.), with 20 patients subsequently enrolled in stage II (etravirine 5.2 mg/kg b.i.d.).

On completion of stage I, an interim analysis of the pharmacokinetic and safety data was performed. Patients enrolled in stage I were able to continue in stage II if they remained eligible; additional patients were recruited to achieve a target enrollment of 20. Patients participating in both stages had a 1-month follow-up period after stage I prior to starting stage II.

Back to Top | Article Outline
Dose selection and administration

The dose of etravirine in stage I was based on allometric scaling of the adult dose [19]. For stage II, the dose was arbitrarily set 30% higher than stage I. Only 25 and 100-mg tablets of etravirine were available; the relative oral bioavailability of the compositionally proportional 25-mg tablet is similar to the 100-mg tablet [20].

Etravirine was to be taken orally, swallowed whole (25 and 100-mg tablets) and taken within 10 min of a meal, every 12 h together with the rest of the antiretroviral regimen.

Back to Top | Article Outline
Blood sampling and nonpharmacokinetic assessments

Plasma viral load (Roche Amplicor HIV-1 Monitor 1.5 UltraSensitive assay; Roche Diagnostics, Mannheim, Germany) was assessed in a central laboratory at screening and on day 8 of each stage. Adverse events were monitored regularly throughout the study and up to 30 days postdose. Blood and urine were collected at screening, on days 1, 5 and 8 of each stage, and at the follow-up visit for evaluation of biochemistry/hematology and urinalysis, respectively. Blood collection was minimized as much as possible and was not to exceed 3 ml/kg in an 8-week period. Blood coagulation and thyroid function were also assessed at screening, on day 8 of each stage, and at follow-up, as coagulation and thyroid disturbances have been observed in nonclinical studies of etravirine [21]. Other safety assessments included physical examination, vital signs and 12-lead ECG.

Back to Top | Article Outline
Pharmacokinetic analysis

Twelve-hour pharmacokinetic sampling was performed on day 8 of treatment, with samples taken predose and 1, 2, 3, 4, 6, 8, 10 and 12-h postdose. Plasma concentrations of etravirine were determined using a validated liquid chromatographic-mass spectrometry/mass spectrometry method (lower limit of quantification: 2.00 ng/ml) [22]. Pharmacokinetic analyses were performed using WinNonlin Professional software (version 4.1; Pharsight Corporation, Mountain View, California, USA), applying a noncompartmental approach with extravascular input (i.e. drug exposure was estimated from the plasma concentration–time curves produced after oral dosing, rather than being based on a model). The minimum and maximum plasma concentrations (Cmin and Cmax, respectively) and time-to-reach Cmax (tmax) were obtained by inspection of the plasma concentration–time profiles. Cmin was the lowest plasma concentration observed within a dosing interval. Area under the plasma concentration–time curve from time of administration to 12 h after dosing (AUC12h) was determined using the linear trapezoidal rule.

Back to Top | Article Outline
Statistical analysis

The decision to recruit at least 10 patients into each age subgroup and dose stage was based on established AUC12h and Cmin values in HIV-1-infected adults. A simulation of 1000 trials showed that recruitment of at least 10 patients into each age subgroup and dose stage would provide an 80% probability that the mean data of the primary pharmacokinetic parameters would be the same as the corresponding parameters in adults (i.e. would provide equal exposure), assuming equal variability (SD).

The efficacy and pharmacokinetic analyses were performed on the intent-to-treat population, with an as-treated analysis performed for the safety parameters. Descriptive statistics are presented for the plasma concentrations of etravirine and the derived pharmacokinetic parameters. Least square mean (LSM) ratios and 90% confidence intervals (CIs) for AUC12h and Cmin were determined.

Comparison of etravirine AUC12h and Cmin data were performed using the pediatric population as test and historic steady-state (day 8) AUC12h and Cmin values from 27 treatment-experienced, HIV-1-infected adults receiving etravirine 200 mg b.i.d. (while on a stable predominantly lopinavir/ritonavir-containing background regimen) as reference [23]. Treatments were declared comparable if the LSM ratios of the primary pharmacokinetic parameters were within 80–125% of the corresponding parameters in adults. Pharmacokinetic parameters were also compared with population pharmacokinetic results from a post-hoc analysis from the DUET-1 and DUET-2 trials; in these trials, the pooled mean (SD) AUC12h and predose plasma concentration (C0h) were 5501 ng h/ml (4544) and 393 ng/ml (378), respectively [10].

In the safety analyses, the type and frequency of adverse events (coded using the Medical Dictionary for Regulatory Activities) and laboratory abnormalities (classified according to the Division of AIDS grading scale) were tabulated; the severity and relatedness of adverse events to etravirine was also described.

Back to Top | Article Outline

Results

The study was conducted at 13 sites across Europe and the United States between September 2006 and February 2008. Twenty-nine patients were screened for stage I. Of these, 21 eligible patients started treatment: 10 in the at least 6 years to less than 12 years subgroup and 11 in the at least 12 years to 17 years or less subgroup. One patient aged at least 12 years to 17 years or less subsequently discontinued stage I prematurely after first etravirine intake due to an adverse event [grade 3 increased creatinine (168 μmol/l, normal range 23–83 μmol/l)] on day 1, reported prior to first intake of etravirine (Figure 1a).

Fig. 1
Fig. 1
Image Tools

An interim analysis conducted after 17 patients had completed stage I revealed pharmacokinetic exposure to 4-mg/kg etravirine b.i.d. was comparable with that seen in HIV-1-infected adults [23]. However, the expected 90% CIs were not met and stage II was, therefore, initiated.

Twenty-six children and adolescents were screened for stage II, of whom 21 were eligible. Twelve patients started treatment in the at least 6 years to less than 12 years subgroup and nine in the at least 12 years to 17 years or less subgroup; all patients completed stage II (Figure 1b). In total, 41 patients completed stage I or II, and seven patients (three aged ≥6 to <12 years and four aged ≥12 to ≤17 years) participated in both stages of the trial.

Back to Top | Article Outline
Baseline characteristics

Baseline characteristics were similar between the two stages of the trial (Table 1). Comparison of the two age subgroups (≥6 to <12 years and ≥12 to ≤17 years) within each stage also showed no significant differences. In stages I and II, the most commonly used NRTIs were lamivudine (62% in each stage), abacavir (33 and 29%, respectively), zidovudine (33% in each stage) and didanosine (29% in each stage).

Table 1
Table 1
Image Tools
Back to Top | Article Outline
Pharmacokinetic results

Pharmacokinetic data were available for 19 and 20 patients in stage I and II, respectively. Three patients (one from stage I and two from stage II) were reported with a major protocol violation (increased dose of etravirine, treatment with a disallowed antiretroviral and failure to carry out a pregnancy test at screening, respectively); only the protocol violation of failure to carry out a pregnancy test at screening was included in the pharmacokinetic analysis.

Median tmax was similar in both stages (Table 2) [10,23]. Mean Cmin, Cmax and AUC12h were higher with the etravirine 5.2 mg/kg b.i.d. dose (stage II) than with the 4 mg/kg b.i.d. dose (stage I). The pharmakokinetic profile for the 12h dosing interval is shown in Figure 2 for both stages.

Table 2
Table 2
Image Tools
Fig. 2
Fig. 2
Image Tools
Back to Top | Article Outline
Comparison of data from children and adolescents with adult reference

Comparison of systemic exposure between children and adolescents dosed with 4 mg/kg b.i.d. showed both the Cmin and AUC12h were similar to adults (LSM ratio 99 and 102%, respectively, Table 2), although interindividual variability was high. In contrast to the 4 mg/kg b.i.d. dose, when dosed at 5.2 mg/kg b.i.d. (stage II), systemic exposure to etravirine (Cmin and AUC12h) was increased by 58% versus adults (Table 2).

Back to Top | Article Outline
Comparison of at least 6 years to less than 12 years and at least 12 years to 17 years age subgroups with adult reference

In stage I, based on LSM ratios, Cmin and AUC12h following etravirine 4 mg/kg b.i.d. were similar between the two age subgroups and the adult reference: at least 6 years to less than 12 years subgroup, 93 (90% CI 54–161) and 108% (90% CI 67–174), respectively; at least 12 years to 17 years or less subgroup, 104 (90% CI 67–161) and 97% (90% CI 67–140), respectively. However, in both cases, the 90% CIs of the LSM ratios of Cmin and AUC12h fell outside the predetermined limits of 80–125%.

The age-stratified analysis of patients dosed at 5.2 mg/kg b.i.d. (stage II) showed that exposure was higher in children than in adolescents, although the variability was large in both age groups. LSM ratios for the comparison of Cmin and AUC12h (5.2 mg/kg b.i.d. versus adult dose) were 183 (90% CI 114–294) and 190% (90% CI 129–282), respectively, in the at least 6 years to less than 12 years subgroup versus 131 (90% CI 82–210) and 126% (90% CI 86–185), respectively, in the at least 12 years to 17 years or less subgroup.

Plasma viral load remained undetectable (HIV-1 RNA <50 copies/ml) throughout the trial in all patients.

Back to Top | Article Outline
Safety and tolerability

No deaths or serious adverse events were reported during the two treatment stages; however, one serious adverse event not related to the study drug (grade 1 influenza leading to hospitalization) was reported during the follow-up period of stage I in a child aged at least 6 years to less than 12 years.

The higher etravirine dose was not linked to an increased risk of adverse events. Overall, 14 patients (67%) in stage I (seven in each age group) and nine patients (43%) in stage II (three aged ≥6 to <12 years and six aged ≥12 to ≤17 years) reported at least one adverse event. The most frequently reported adverse events were headache (three patients in each stage; one aged ≥6 to <12 years and two aged ≥12 to ≤17 years) and rhinitis (two patients in each stage and one in each age group).

All adverse events were grade 1 or 2 in severity with the exception of one grade 3 adverse event [stage I, increased creatinine (not related; patient withdrawn from trial), predose on day 1] and one grade 4 adverse event (stage II, increased triglycerides, detected on day 8, namely after the last intake of drug, considered probably related to etravirine and possibly related to the background regimen). Adverse events considered to be at least possibly related to etravirine were reported in five patients (24%) in stage I and six patients (29%) in stage II; treatment-related adverse events of severity of at least grade 2 are shown in Table 3.

Table 3
Table 3
Image Tools

Apart from the patient mentioned above, there were no other discontinuations due to adverse events reported during the two treatment stages. Three patients reported skin events of interest: grade 2 maculopapular rash (on day 8 of stage I, very likely related to etravirine); grade 1 rash (on day 8 of stage I, probably related to etravirine) and grade 1 erythema (on day 1 of stage II, not related to etravirine). Both cases of rash resolved with continued treatment (hydroxyzine and dimetindene maleate, respectively) within a few days.

The most common treatment-emergent laboratory abnormalities in stages I and II were increases in total cholesterol (30 versus 24%), low-density lipoprotein (LDL) cholesterol (45 versus 10%) and glucose (15 versus 5%). All treatment-emergent graded laboratory abnormalities were grade 1 or 2, except for a grade 3 increase in LDL cholesterol and total cholesterol, each observed in one patient. With two exceptions, there were no consistent or clinically relevant changes from baseline in any laboratory parameter reported in either stage, with the exception of one patient in stage I who was reported with a grade 3 increase in creatinine in the predose sample on day 1 and was withdrawn from the study after the first dose of etravirine, and one patient in stage II who developed a grade 4 increased triglyceride level after the intake of 5.2 mg/kg (200 mg) etravirine on day 8; at the follow-up visit on day 36, this had decreased to grade 2. No clinically relevant changes from baseline in vital signs or ECG parameters were reported.

Back to Top | Article Outline

Discussion

Appropriate management of HIV-infected pediatric patients is particularly important, especially given the requirement for treatment during critical phases of growth and development, as well as the lifelong need for therapy. In addition, the challenge of developing suitable pediatric formulations and the limited number of antiretroviral agents registered for children limit the therapeutic options for the pediatric population. Etravirine retains antiretroviral activity in the presence of mutations that would normally confer resistance to first-generation NNRTIs [24,25] and, thus, may provide potential benefits for HIV-1-infected, treatment-experienced pediatric patients.

This study was designed to evaluate the pharmacokinetics of etravirine in children and adolescents aged at least 6 years to 17 years or less. In the present study, mean exposures achieved with the 4 mg/kg b.i.d. dose of etravirine were largely comparable with those seen in treatment-experienced adults receiving etravirine 200 mg b.i.d. (with lopinavir/ritonavir and at least one NRTI, with or without enfuvirtide) over the same 8-day dosing period [23], according to the prespecified criteria for comparability. However, the 90% CIs were outside the 80–125% limits for both Cmin and AUC12h. As no major safety or tolerability concerns were identified in the interim analysis and, in light of the concerns regarding general underdosing in children, stage II was, therefore, initiated with an etravirine dose of 5.2 mg/kg b.i.d.

Exposures achieved with the 5.2 mg/kg b.i.d. dose of etravirine were higher than those seen in the adult reference trial [23], and both the LSM ratios and upper limits of the 90% CIs were outside 80–125% threshold for comparability for Cmin and AUC12h.

The exposure of etravirine when administered as 4 or as 5.2 mg/kg b.i.d. was higher in children (≥6 to <12 years) compared with adolescents (≥12 to ≤17 years). This result was mainly due to one patient in the younger age group who participated in both stages and who had consistently high exposures to etravirine at both doses; it is, therefore, unlikely to be clinically relevant.

As commonly observed in pediatric antiretroviral pharmacokinetic studies, the interindividual variability in the pharmacokinetic parameters was high [15,26]. This probably reflects individual differences in absorption, distribution, metabolism and excretion, a common condition in pediatric patients [15]. The fact that the lower limits of the 90% CIs fell within the 80–125% threshold for comparability with adults for Cmin and AUC12h suggests that the 5.2 mg/kg b.i.d. dose is unlikely to lead to underdosing in children. As expected, viral load remained undetectable in all patients throughout the trial.

Both doses of etravirine were shown to be generally safe and well tolerated, with no serious adverse events or discontinuations due to adverse events reported during treatment. The short-term safety and tolerability profile of etravirine in children and adolescents was very similar to that reported in the adult reference study [23], with the caveat that the results are based on 1 week of treatment.

The main objective of the trial was to determine the optimal dose of etravirine in children and adolescents, and not the efficacy or long-term safety. Therefore, the study was primarily designed to reduce the risk of underdosing and the possibility of selecting for resistant strains. For this reason, we believe that adding a new antiretroviral agent to an existing effective antiretroviral regimen is a viable option for studies aiming to determine the optimal dose of investigational drugs. The sample size in each age-stratified subgroup was small, but enough to determine an appropriate dose, even given the high interindividual variability.

Two recent publications have focused on the efficacy of etravirine in treatment-experienced children. A case study reported that when an infant who was failing on a protease inhibitor-based regimen was switched to a regimen containing etravirine (50 mg b.i.d., increasing to 100 mg b.i.d. after 2 months) and darunavir/ritonavir (150/20 mg b.i.d.) (both supplied through a compassionate use program), viral load decreased sharply (from 5.38 to 2.27 log10 copies/ml), reaching and maintaining undetectable levels between 12 and 15 months of follow-up. This was coupled with an increase in CD4 cell count in the first 6 months of treatment, from 14 to 1294 cells/μl, which was also maintained at 15 months of follow-up [27]. More recently, Briz et al. described a small cohort of HIV-infected, treatment-experienced children (n = 5) and adolescents (n = 18) treated with etravirine 5.2 mg/kg b.i.d. and other antiretroviral drugs (91% having at least two fully active antiretrovirals in their regimen). Twenty (87%) participants achieved HIV-1 RNA viral load less than 400 copies/ml and 18 (78%) achieved HIV-1 RNA viral load less than 50 copies/ml: three (13%) within the first month, 11 (48%) within the first 4 months and the remainder within the first 8 months [28]. A further study is ongoing to determine the long-term safety and efficacy of etravirine in children and adolescents (PIANO, NCT00665847). Results from the 24-week analysis suggest the 5.2 mg/kg b.i.d. dose of etravirine is appropriate, efficacious, safe and well tolerated [29,30].

In summary, etravirine administered at both 4 and 5.2 mg/kg b.i.d. to HIV-1-infected children and adolescents (aged ≥6 to ≤17 years) provides exposures similar to etravirine 200 mg b.i.d. in treatment-experienced, HIV-1-infected adults. Etravirine 5.2 mg/kg was well tolerated in this study and, based on the general concern for underdosing of antiretroviral drugs in children [15,26,31–33] and given the overall favorable safety and tolerability profile of the higher dose, etravirine 5.2 mg/kg b.i.d. was selected as the dose for further investigation in the PIANO study.

Back to Top | Article Outline

Acknowledgements

R.R. passed away during the development of this manuscript. The author reviewed the outline and first draft in detail for clinical accuracy and intellectual content.

The authors would like to thank the patients and their parents/legal guardians for their participation in the study, study center staff, particularly Irene Picciolli, Caterina Sabatini and Margherita Semino, Richard Linde and Kai Beuckmann, and Tibotec study personnel for their support during the trial. They also acknowledge David Anderson, Benny Baeten, Goedele De Smedt, Eric Lefebvre, Steven Nijs, Frank Tomaka and Katrien Janssen for their important contributions to the manuscript. In addition, the authors would like to acknowledge Karen Pilgram (Senior Medical Writer at Gardiner-Caldwell Communications, Macclesfield, UK) for assistance in drafting the manuscript and collating author contributions.

Support for medical writing services, carried out by Gardiner-Caldwell Communications, was provided by Tibotec Pharmaceuticals.

Back to Top | Article Outline
Conflicts of interest

This study was sponsored by Tibotec Pharmaceuticals.

All study investigators received research funding from Tibotec to support their patients’ participation in this trial. C.K. has received research funding for clinical trials from Abbott, Bristol Meyers Squibb, Boehringer Ingelheim and Tibotec. C.V. has received grant money from Tibotec and Janssen and has acted as a board member, consultant and speaker for Pfizer, Gilead Sciences, Merck, Astellas and Schering-Plough. S.E. has received grant money from Tibotec. C.F.-S. has received grant money and support for travel to meetings from Tibotec. T.N.K., M.P., I.P., R.S., R.M. and K.B. are all full-time employees of the trial sponsor, Tibotec. R.L. is a full-time employee of Johnson & Johnson Pharmaceutical Research and Development.

C.G. and R.R. declare no further conflict of interest.

Back to Top | Article Outline

References

1. Phelps BR, Rakhmanina N. Antiretroviral drugs in pediatric HIV-infected patients: pharmacokinetic and practical challenges. Paediatr Drugs 2011; 13:175–192.

2. PENTA Steering Committee. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection.HIV Med 2009; 10:591–613.

3. World Health Organization. Antiretroviral therapy of HIV infection in infants and children: towards universal access – recommendations for a public health approach. 2010 revision. 2010. http://www.who.int/entity/hiv/pub/children/9789241548083/en/index.html. [Accessed 14 April 2011]

4. Department of Health and Human Services (DHHS). Panel on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 2011. http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf. pp. 1–268. [Accessed 24 August 2011].

5. Department of Health and Human Services (DHHS). Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2011. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. [Accessed 14 April 2011].

6. Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:39–48.

7. Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370:29–38.

8. Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS 2009; 23:2289–2300.

9. Katlama C, Clotet B, Mills A, Trottier B, Molina JM, Grinsztejn B, et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther 2010; 15:1045–1052.

10. Kakuda TN, Wade JR, Snoeck E, Vis P, Schöller-Gyüre M, Peeters MP, et al. Pharmacokinetics and pharmacodynamics of the nonnucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther 2010; 88:695–703.

11. Salazar JC, Cahn P, Yogev R, Negra MD, Castelli-Gattinara G, Fortuny C, et al. Efficacy, safety and tolerability of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents. AIDS 2008; 22:1789–1798.

12. Blanche S, Bologna R, Cahn P, Rugina S, Flynn P, Fortuny C, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS 2009; 23:2005–2013.

13. Starr SE, Fletcher CV, Spector SA, Brundage RC, Yong FH, Douglas SD, et al. Efavirenz liquid formulation in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2002; 21:659–663.

14. von Hentig N, Koenigs C, Elanjikal S, Linde R, Dunsch D, Kreuz W, et al. Need for therapeutic drug monitoring in HIV-1 infected children receiving efavirenz doses according to international guidelines. Eur J Med Res 2006; 11:377–380.

15. Menson EN, Walker AS, Sharland M, Wells C, Tudor-Williams G, Riordan FA, et al. Underdosing of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing medicines to children, 1997–2005: cohort study. BMJ 2006; 332:1183–1187.

16. Fisher CB, Kornetsky SZ, Prentice ED. Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations. Am J Bioethics 2007; 7:5–10.

17. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention growth charts. http://www.cdc.gov/growthcharts/Default.htm. [Accessed 14 April 2011]

18. Division of Acquired Immune Deficiency Syndrome (DAIDS). Table for Grading the Severity of Adult and Pediatric Adverse Events, December 2004. (http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_Pediatric_Adverse_Events.pdf)

19. Meibohm B, Läer S, Panetta JC, Barrett JS. Population pharmacokinetic studies in pediatrics: issues in design and analysis. AAPS J 2005; 7:E475–E487.

20. Schöller-Gyüre M, Kakuda TN, Van Solingen-Ristea RM, Berckmans C, De Smedt G, Peeters M, et al. Bioavailability of the 100mg etravirine tablet dispersed in water and of the 25mg pediatric tablet formulation [abstract MOPE0184]. In: 17th International AIDS Conference; 3–6 August 2008; Mexico City, Mexico.

21. De Jonghe S, Verbeeck J, Vinken P, Lammens L, Starckx S, Lachau-Durand S, et al. Hemorrhagic cardiomyopathy in male mice treated with an NNRTI: the role of vitamin K. Toxicol Pathol 2008; 36:321–329.

22. Schöller-Gyüre M, Kakuda TN, Sekar V, Woodfall B, De Smedt G, Lefebvre E, et al. Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Antivir Ther 2007; 12:789–796.

23. Kakuda TN, Schöller-Gyüre M, Workman C, Arasteh K, Pozniak AL, De Smedt G, et al. Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients. Antivir Ther 2008; 13:655–661.

24. Andries K, Azijn H, Thielemans T, Ludovici D, Kukla M, Heeres J, et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48:4680–4686.

25. Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 2005; 79:12773–12782.

26. Verweel G, Burger DM, Sheehan NL, Bergshoeff AS, Warris A, van der Knaap LC, et al. Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below. Antivir Ther 2007; 12:453–458.

27. Viganò A, Meroni L, Marchetti G, Vanzulli A, Giacomet V, Fasan S, et al. Successful rescue therapy with a darunavir/ritonavir and etravirine antiretroviral regimen in a child with vertically acquired multidrug-resistant HIV-1. Antivir Ther 2008; 13:839–843.

28. Briz V, Palladino C, Navarro M, Jiménez de Ory S, González-Tomé M, León J, et al. Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients. HIV Med 2011; 12:442–446.

29. Kakuda TN, Green B, Morrish G, Brochot A, Nijs S, Vis P. Population pharmacokinetics of etravirine in HIV-1-infected, treatment-experienced children and adolescents (6 to <18 years) [abstract TULBPE026]. In: 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 17–20 July 2011; Rome, Italy.

30. Tudor-Williams G, Cahn P, Chokephaibulkit K, Fourie J, Karatzios C, Dincq S, et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents (6 to <18 years): week 24 primary analysis of the phase II PIANO study [abstract TULBPE027]. In: 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 17–20 July 2011; Rome, Italy.

31. ter Heine R, Scherpbier HJ, Crommentuyn KM, Bekker V, Beijnen JH, Kuijpers TW, et al. A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations. Antivir Ther 2008; 13:779–787.

32. Hirt D, Urien S, Olivier M, Peyrière H, Nacro B, Diagbouga S, et al. Is the recommended dose of efavirenz optimal in young West African human immunodeficiency virus-infected children?. Antimicrob Agents Chemother 2009; 53:4407–4413.

33. Ren Y, Nuttall JJC, Egbers C, Eley BS, Meyers TM, Smith PJ, et al. High prevalence of subtherapeutic plasma concentrations of efavirenz in children. J Acquired Immune Defic Syndr 2007; 45:133–136.

Keywords:

children; etravirine; HIV-1; pediatric; pharmacokinetics; phase I

© 2012 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.