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Pharmacokinetics of Pediatric Lopinavir/Ritonavir Tablets in Children When Administered Twice Daily According to FDA Weight Bands

Bastiaans, Diane E. T. PharmD*; Forcat, Silvia PharmD, PhD; Lyall, Hermione MB ChB(Hons), MD, FRCPCH; Cressey, Tim R. PhD§; Hansudewechakul, Rawiwan MD; Kanjanavanit, Suparat MD; Noguera-Julian, Antoni MD, PhD**; Königs, Christoph MD††; Inshaw, Jamie R. J. MSc; Chalermpantmetagul, Suwalai RN, MSc§; Saïdi, Yacine PhD‡‡; Compagnucci, Alexandra MD‡‡; Harper, Lynda M. MSc; Giaquinto, Carlo MD§§; Colbers, Angela P. H. MSc*; Burger, David M. PharmD, PhD* on Behalf of PENTA 18KONCERT Study Group

Author Information
The Pediatric Infectious Disease Journal: March 2014 - Volume 33 - Issue 3 - p 301-305
doi: 10.1097/INF.0000000000000014

Abstract

HIV-infected children require lifelong treatment with combination antiretroviral therapy (cART). Currently, the preferred cART regimen recommended for antiretroviral treatment–naive children with no resistance to antiretroviral drugs comprises a backbone of 2 nucleoside reverse transcriptase inhibitors plus either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir (RTV)-boosted protease inhibitor.1–3

Lopinavir boosted with low-dose ritonavir (LPV/r) is used worldwide in HIV-infected children as part of first- and second-line treatments.1,2 It is licensed to be taken twice daily for children from the age of 2 years by the European Medicines Agency (EMA) and from the age of 14 days by the United States Food and Drug Administration (FDA). There are several LPV/r formulations available: a liquid formulation (LPV/r 80/20 mg/mL), adult tablets (LPV/r 200/50 mg) and pediatric tablets (LPV/r 100/25 mg). The pediatric tablet (100/25 mg) was approved by the FDA in 2007 and by the EMA in 2008; however, the posology in the product labels approved by these 2 agencies is not the same. The dose for an individual is based on body surface area only as recommended by the EMA, while it is based on body weight bands or body surface area as recommended by the FDA. Dosing based on body weight bands versus body surface area may lead to differences in the number of tablets recommended for a child with a certain weight, which is confusing and undesirable from a global perspective. The FDA-recommended weight band dosing has been derived from pharmacokinetic (PK) modeling but has not been formally studied in the target population. To validate the FDA weight band–based dosing recommendations, we evaluated the PK of LPV/r administered twice daily, using the pediatric 100/25 mg tablet, in HIV-infected children.

METHODS

This PK study is part of the ongoing Paediatric European Network for the Treatment of AIDS (PENTA)-18 trial or KONCERT trial: A Kaletra ONCE daily Randomized Trial of the pharmacokinetics, safety and efficacy of twice-daily versus once-daily lopinavir/ritonavir tablets dosed by weight as part of combination antiretroviral therapy in HIV-1 infected children (NCT01196195). KONCERT is a phase II/III, prospective, randomized, open-label, international, multicenter trial in virologically suppressed HIV-1–infected children. Children were eligible when they were younger than 18 years, ≥15 kg in weight, receiving cART that includes LPV/r and had an HIV-1 RNA <50 copies/mL for at least 24 weeks and were able to swallow tablets. Children receiving an NNRTI or a PI other than LPV/r were excluded. The use of concomitant drugs, except for prophylaxis, was not allowed unless permission was granted by the trial team. Children were randomized (1:1) to either continue the same ART regimen with LPV/r tablets taken twice-daily (n = 80) or to switch to LPV/r tablets dosed once daily (n = 80). The KONCERT trial has been approved by the regulatory bodies and ethics committees for all participating countries and sites. KONCERT is being conducted in full conformance with the principles of the current version of the Declaration of Helsinki and with the local laws and regulations concerning clinical trials.

Population and Treatment

Children were enrolled in KONCERT in one of three weight bands: ≥15 to ≤25 kg (low), >25 to ≤35 kg (middle) and >35 kg body weight (high). In the first phase of the trial, children who consented were selected to participate in a PK substudy, until a minimum of 16 children in each weight band had evaluable PK data. If needed, the LPV/r formulation was changed to the pediatric tablet at the screening visit and the dose adjusted to follow the recommended FDA dosing plan based on body weight bands (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/B688). It was required that tablets be swallowed whole and could be taken with or without food. Adherence was assessed by pill counts and a questionnaire at screening and on the day of the PK assessment. During the trial, an amendment to the protocol was made to ensure ethnic representativeness within the PK study. At that time, the highest weight band already had 12 children from Thailand and further inclusion into the PK study from this country was stopped. Enrollment of subsequent participants continued to have 8 children from countries other than Thailand in each of the weight bands.

Sample Size

Based on plasma LPV PK data from an adult study on tablet formulation, the estimated variance of log10 area under the curve (AUC) for pediatric tablets was approximately 0.2 (internal Abbott data). Forty-eight children (16 in each weight band) providing plasma LPV PK data on twice-daily tablet regimens was estimated to provide at least 80% power for the width of the 90% confidence interval for the mean log10 AUC on twice-daily dosing to be <0.230 on the log10 scale. Therefore, to confirm FDA body weight–based dosing recommendations of twice-daily LPV/r 100/25 mg tablets, 48 children was considered to be sufficient for the estimation of interpatient variability.

PK Assessment

Full 12-hour PK assessment of LPV/r was conducted prior to randomization. Children must have been receiving the pediatric tablets twice daily at the FDA-recommended weight band–based dose for at least 7 days prior to the PK assessment. On the PK day, the child’s medications were intended to be administered before taking breakfast. Depending on the country and hospital, breakfast according to local custom was served (eg, pork/chicken/fish soup, rice and a cup of milk; cereal, toast, cooked eggs and scones; or bread roll with butter, ham, cheese, jam or hazelnut spread). Blood samples (2 mL/time point) were taken in ethylenediaminetetraacetic acid (EDTA) tubes at 0 (predose, before morning dose), 2, 4, 6, 8 and 12 hours after an observed intake.

Pharmacokinetics

Lopinavir (LPV) and RTV PK parameters were determined using noncompartmental analysis (WinNonlin®, version 5.3., Pharsight® Corporation, Mountain View, CA): AUC0–12 (area under the plasma concentration-time curve calculated (linear-log trapezoidal method) over a dosing interval from time 0 to 12 hours after dosing), Cmax (maximum observed plasma concentration) and C12 (drug concentration 12 hours postdose).

Measurement of Plasma Drug Concentration

Samples were processed within 3 days of collection, and plasma was stored immediately at −80°C. Plasma concentrations of LPV and RTV were determined using a validated ultrahigh performance liquid chromatography assay with ultraviolet detection derived from the previously published assay.4 The analysis was performed at the Department of Pharmacy, Radboud University Nijmegen Medical Centre, and this laboratory participates in an international interlaboratory quality control program for therapeutic drug monitoring of antiretroviral drugs.5 The analytical range of the assay for LPV was 0.109–31.2 mg/L and for RTV 0.044–29.4 mg/L. The intraday and interday precision for both assays ranged from 0.6% to 4.2% (coefficient of variation) and 0.3% to 1.8%, respectively. The percentage accuracy of the assay ranged from 98.2% to 105.6%.

Statistical Analysis

To validate dosing by the FDA weight bands, linear regression of the PK parameters against dose (mg/kg body weight) was performed. Analysis of variance (ANOVA) was used to compare the geometric means of each PK parameter between the three different weight bands. This was further tested by regression of log-transformed parameters against weight as a continuous variable. Comparison of the PK parameters between different ethnic groups (Asian vs. non-Asian children) was performed using an independent t test on log-transformed values. Statistical analysis was performed using SPSS software version 20.0.0.1 (SAS Institute, Cary, NC).

RESULTS

Population

Fifty-three children were enrolled in the PK study between August 2010 and December 2011: 17, 16 and 20 children in the 15 to ≤25 kg, >25 to ≤35 kg and >35 kg weight bands, respectively. Median (range) age of the children was 11.0 (4.4–17.7) years. Twenty-two (42%) were male children. Further demographic data of the patients are presented in Table 1.

TABLE 1
TABLE 1:
Demographic Data of Children in KONCERT Pharmacokinetic Substudy

The use of concomitant medication was reported for 5 children. According to the literature, none of the concomitant medication used is known to influence the metabolism of LPV or RTV. No use of natural products or herbs was reported. None of the children vomited either the day before or on the day of the PK assessment. The median (range) LPV dose taken by the children was 9.8 (5.5–13.3) mg/kg or 270 (215–329) mg/m2.

Lopinavir PK

For the total group, the LPV geometric mean (95% CI) AUC0–12 was 106.9 (97.8–116.9) h × mg/L, Cmax 12.0 (11.1–12.9) mg/L and C12 was 4.9 (4.1–5.8) mg/L. The geometric mean plasma LPV concentration-time profile for the total group and the profiles per weight band are shown in Figure 1. The geometric means of the PK parameters for each weight band and the total group are presented in Table 2.

TABLE 2
TABLE 2:
Pharmacokinetic Parameters of Lopinavir and Ritonavir
FIGURE 1
FIGURE 1:
Plasma lopinavir concentration versus time for the total group and for each weight band (data are presented as geometric means).

Because the PK parameters of LPV were not normally distributed, statistical analysis was performed on the log-transformed data. Linear regression showed no correlation of the LPV PK parameters AUC0–12 (P = 0.062), C12 (P = 0.87) and CL/F (P = 0.20) against the weight-based dose (mg/kg body weight). Linear regression did show a correlation between the weight-based dose of LPV and Cmax (P = 0.039).

There were no significant differences when comparing LPV PK parameters between the weight bands (AUC0–12, P = 0.42; Cmax, P = 0.17; C12, P = 0.46 and CL/F, P = 0.75). Weight was also not associated with variability in the LPV PK parameters (AUC0–12, P = 0.44; Cmax, P = 0.12; C12P = 0.33 and CL/F, P = 0.25).

One of the 53 children (1.9%) had an LPV C12 < 1.0 mg/L (0.56 mg/L). This child received an LPV dose of 11.5 mg/kg, which was higher than the median value in this study (9.8 mg/kg). Remarkably, the predose morning level of this child was 8.1 mg/L. The last dose was reported to be taken approximately 12 hours prior to the observed intake on the day of PK assessment. No explanation could be found for this difference, other than the possible diurnal variation in absorption, distribution, metabolism and excretion.6

Given the high percentage of Asian children within the PK study population, it was tested whether there was a difference in PK parameters between Asian and non-Asian children. Significant influence of ethnicity was found on CL/F (P = 0.021), with Asian children having a higher clearance. There were no significant differences in the other PK parameters between Asian and non-Asian children (AUC0–12, P = 0.17; Cmax, P = 0.089 and C12, P = 0.18). The geometric mean plasma LPV concentration-time profiles for the Asian children and non-Asian children are shown in Figure 2.

FIGURE 2
FIGURE 2:
Plasma lopinavir concentration versus time of Asian and non-Asian children (data are presented as geometric means and error bars show standard error of the mean).

DISCUSSION

This study conducted in 53 HIV-infected children found adequate LPV exposure when LPV/r 100/25 mg tablets were administered according to the FDA-recommended weight band–based dose. No significant differences of PK parameters for LPV were observed between the three weight bands. The current recommendation for the LPV trough concentration in HIV-infected patients with no evidence of resistance is 1.0 mg/L.3 Fifty-two (98%) of the children achieved a trough concentration of 1.0 mg/L or higher. Therefore, the weight band–based dosing described by the FDA can be used to treat HIV-infected children with the LPV/r pediatric tablets.

In this study, the geometric mean LPV AUC0–12 was 106.9 h × mg/L, Cmax 12.0 mg/L and C12 4.9 mg/L. The LPV AUC0–12, Cmax and C12 were all higher than that observed in children receiving 230/57.5 mg/m2 of the LPV/r solution described in the summary of product characteristics (AUC0–12 72.6 h × mg/L, Cmax 8.2 mg/L and C12 3.4 mg/L).7 This can mostly be explained by the higher dose that is used in our population (median dose 270 mg/m2). The clinical relevance of this higher exposure (ie, side effects) is being assessed in the ongoing main trial. A summary of LPV/r PK parameters reported from 10 studies in HIV-infected children (n > 10) is shown in Table, Supplemental Digital Content 2, https://links.lww.com/INF/B689.7–15 Studies in which some of the children used an NNRTI are included, but unfortunately results were not always specified for concomitant use of an NNRTI. When comparing results of these PK studies, it is important to realize that different formulations of LPV/r may have been used, which could lead to differences in PK parameters. The AUCtau and AUC of the soft gel capsule and oral solution are 18% lower compared with the 200/50 mg tablet formulation in healthy volunteers, although the 90% CI of the geometric mean ratio is within the bioequivalence range of 80%–125%.16 A study in HIV-infected adults showed that the mean Clast was higher with a generic tablet compared with the soft gel capsule formulation.17 A 45% decrease in LPV AUC0–12 was observed in HIV-infected children when LPV/r tablets were crushed compared with administration of whole tablets.8 The formulation used is also significantly associated with the absorption lag time: the lag time in HIV-infected children using the solution was half the lag time in children using capsules.13 PK parameters found in a study evaluating the PK of LPV/r in Thai adolescents using the 200/50 mg tablet formulation were comparable with our results.11

Diet can also influence the PK of LPV. Differences in LPV AUCtau and Cmax have been shown when the LPV/r tablet formulation is administered under fasting conditions or with a moderate or high-fat meal. Compared with administration of LPV/r under fasting conditions, the LPV AUCtau and Cmax increased, respectively, by 26.9% and 17.6%, with a moderate-fat meal. When administered with a high-fat meal, the LPV AUCtau increased by 18.9% and Cmax was unchanged.16

This is the first PK study in which the PK parameters of LPV in a large group of Asian children can be directly compared with the results of children of other ethnic origins. However, this should be done with caution because the baseline characteristics of both groups are different. Mean age of the Asian patients is significantly higher than that of non-Asian patients. Furthermore, the weight for age is significantly lower in the Asian children. Regarding the PK parameters, a significant difference in LPV clearance (CL/F) was observed between Asian and non-Asian children. The CL/F of LPV in Asian children was on average 21% higher than in non-Asian children: 0.097 versus 0.080 L/h × kg (P = 0.021). This result was unexpected, as usually lower clearance is expected, and therefore, a lower LPV/r dose has previously been investigated in Thai children.11,12 However, plasma half-life of LPV of Asian and non-Asian children was the same for both groups (6.5 hours). A comparison of CL/F of Thai children and a group of mainly (78%) African American children showed similar clearance in both groups: median (IQR) CL/F 1.7 (1.0–3.5) and 1.8 (1.0–2.6) L/h, respectively.12,13,18 Despite the significantly higher CL/F in Asian children in our study, there was no significant difference in AUC0–12 between Asian and non-Asian children, which can be explained by the relatively higher dose in the Asian children on a mg/kg basis [9.8 vs. 9.1 mg/kg (median dose)]. A possible explanation for these observations could be a difference in diet and more Asian children in our study taking their medication under fasting conditions at the day of PK assessment: 52% versus 13% of the non-Asian children. Differences between ethnic groups in expression of cytochrome P450A (CYP3A) isoenzymes could explain interpatient variability in the PK of LPV.14,19–21 For instance, wild-type CYP3A, which is associated with more rapid metabolism, is more frequently expressed in Southeast Asians compared with Caucasians.22–24 Another mechanism possibly involved in the PK of LPV relates to transporter proteins, such as the permeability glycoprotein (P-gp; MDR1, ABCB1), the multidrug resistance protein 2 (MRP2; ABCC2) and the organic anion transporters (OATP; SLCO1B1).14,20,21,25–28 Genotype frequencies of these transporter proteins differ between ethnic groups,29,30 but data from Asian patients are lacking. Unfortunately, no genetic testing was performed in our patients, and the influence of these polymorphisms on the PK of LPV cannot be explored. It must be noted that despite potential ethnic influences on LPV PK, exposure in all subgroups was adequate.

In conclusion, FDA weight band-based dosing recommendations provide adequate exposure when using the pediatric LPV/r tablets. Hence, the FDA-recommended dose for the weight bands of ≥15 to ≤25 kg, >25 to ≤35 kg and >35 kg body weight can be used to achieve adequate exposure of LPV in HIV-infected children.

ACKNOWLEDGMENTS

We thank all the children and their families, staff from the centers participating in the KONCERT trial and investigators who included their patients in this PK study.

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Keywords:

lopinavir; ritonavir; pharmacokinetics; pediatric tablets; HIV

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