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**|**Antimicrob Agents Chemother**|**v.55(7); 2011 July**|**PMC3122471

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Antimicrob Agents Chemother. 2011 July; 55(7): 3498–3504.

doi: 10.1128/AAC.01622-10

PMCID: PMC3122471

Naïm Bouazza,^{1,}^{2,}^{*} Déborah Hirt,^{1,}^{2} Stéphane Blanche,^{1,}^{5} Pierre Frange,^{1,}^{5} Elisabeth Rey,^{3} Jean-Marc Tréluyer,^{1,}^{2,}^{3,}^{4} and Saik Urien^{1,}^{2,}^{4}

Received 2010 November 22; Revisions requested 2011 April 16; Accepted 2011 April 28.

Copyright © 2011, American Society for Microbiology

This article has been cited by other articles in PMC.

Lamivudine concentration-time courses were described for a very large range of ages to study the effects of body weight and maturation on lamivudine pharmacokinetics and to check the consistency of dosing recommendations. Lamivudine concentrations were monitored on a routine basis to produce concentrations similar to the known values in adults. Concentrations were measured in 580 children from 2 days to 18 years old. A total of 2,106 plasma lamivudine concentrations were measured, and a population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.1 software. A two-compartment model adequately described the data. After standardization for a mean standard body weight by using an allometric model, age also had a significant effect on clearance maturation. Typical population estimates (percent interindividual variability) standardized for 70 kg of the apparent clearance, including central and peripheral volumes of distribution, intercompartmental clearance, and absorption rate constant, were 31 liters·h^{−1} (32%), 76.4 liters (77%), 129 liters, 5.83 liters·h^{−1}, and 0.432 h^{−1}, respectively. According to the model, elimination clearance (liters/h/70 kg) increases gradually during the first years of life. Theoretical doses needed to reach the range of 24 h of exposure observed in adults were calculated: to be closer to adult exposure, children should receive 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.

Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor (NRTI). Following an oral dose, lamivudine is rapidly absorbed and has a wide distribution due to its relatively low molecular mass (229 Da) and low plasma protein binding (<36%). The majority of lamivudine (approximately 70%) is eliminated unchanged in the urine over 24 h (12). Approximately 5 to 10% is metabolized to the pharmacologically inactive *trans*-sulfoxide metabolite, the majority of which is also excreted in the urine within 12 h after a single oral dose (12).

Lamivudine is used for treatment of human immunodeficiency virus type 1 (HIV-1) infection in a very wide range of ages, from neonates to adults. Although the pharmacokinetics is quite well described in adults, limited studies are available on lamivudine pharmacokinetics in very young children. Dosing recommendations are based on the hypothesis of the immaturity of renal function in newborns; thereby, the usual standard lamivudine dose is 4 mg/kg of body weight/day within 6 weeks after birth and 8 mg/kg/day thereafter (24). For older children, the current recommended doses are 150 mg/day from 14 to 21 kg, 225 mg/day from 21 to 30 kg, and 300 mg/day thereafter (24). In the present study, we have developed a population pharmacokinetic model for lamivudine in a large group of children from neonates to adolescents in order to determine the relationship between lamivudine pharmacokinetics and age or body weight and to investigate the consistency of the current recommended pediatric dosage regimen.

The population comprised 580 pediatric patients, ranging in age from 2 days to 18 years (median, 7.41 years) and in body weight from 1 to 84 kg (median, 23 kg). Children received lamivudine as tablet or oral solution for the treatment of HIV infection or for the prevention of mother-to-child transmission. The median (standard deviation [SD]) lamivudine dose was 7.5 (3.2) mg kg^{−1}/day. Ethics committee approval and patient consent are not compulsory in France in order to retrospectively use therapeutic drug monitoring data, so no informed consent had to be collected.

Lamivudine was measured in a 100–μl plasma sample by high-performance liquid chromatography. An internal standard was used. Lamivudine was extracted by solid-phase extraction on a Bond Elut C_{18} column, and separated on a Satisfaction C_{8} Plus column (250 by 3 mm) with a gradient of solvent A (water with 0.01% trifluoroacetic acid, 2% methanol, and 3% acetonitrile) and solvent B (acetonitrile) as follows: 50% solvent A and 50% solvent B for 30 min, 90% solvent A and 10% solvent B for 30 min, and 98% solvent A and 2% solvent B for 30 min. UV absorbance at 270 nm was used for detection the detection of lamivudine. The limit of quantification (LOQ) was 0.02 mg/liter. The mean interassay precision at the low-quantity controls was 10%, and inaccuracy at the LOQ was 4.5%. Overall recovery was 65%.

Data were analyzed using the nonlinear mixed effect modeling software program Monolix, version 31s (http://wfn.software.monolix.org) (14). Parameters were estimated by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization) using the stochastic approximation expectation maximization (SAEM) algorithm combined with a Markov chain Monte Carlo (MCMC) procedure. The number of MCMC chains was fixed to 10 for all estimations. The between-subject variabilities (BSV [η]) were ascribed to an exponential model. Parameter shrinkage was calculated as {1 − SD(η)/ω}, where SD(η) and ω are the standard deviation of individual η parameters and the population model estimate of the BSV, respectively (22). The likelihood ratio test (LRT) including the log likelihood, the Akaike information criterion (AIC), and the Bayesian information criterion (BIC) were used to test different hypotheses regarding the final model, covariate effects on pharmacokinetic parameters, the residual variability model (proportional versus proportional plus additive error model), and the structure of the variance-covariance matrix for the BSV parameters.

The main covariates of interest in the population were postnatal age (PNA), body weight, postmenstrual age (PMA; PMA = PNA + gestational age), and the formulation. Gestational age has been set to 40 weeks when the information was not available. Age-related change functions for clearance (CL) or volume of distribution (*V*) as a function of PNA or postmenstrual age have been described in detail (2, 9, 21).

Parameter estimates were standardized for a mean standard body weight by using the allometric model *P _{i}* =

Galenic form was tested as a categorical covariable (CA) on bioavailability in order to point out a difference between oral tablet and solution according to CL = θ_{CL} × β^{CA}. For evaluation of the goodness of fit, the following graphs were performed for the final model: observed and predicted concentrations versus time, observed concentrations versus population predictions, weighted residuals versus time, and weighted residuals versus predictions. Similar graphs using individual predictive estimation were examined. Diagnostic graphics were obtained using the R program (11). A repeated-measures analysis of variance (ANOVA), performed using the nlme package (20) with the R program, was used to test possible differences between a once-a-day (OAD) regimen and a twice-a-day (BID) regimen.

Lamivudine concentration profiles were simulated and compared with the observed data to evaluate the predictive performance of the model. Simulated concentrations were then compared with the observed data to evaluate the predictive performance of the model. The vector of pharmacokinetic parameters was simulated by using the final model. Each vector parameter was drawn in a log-normal distribution with a variance corresponding to the BSV previously estimated. A simulated residual error was added to each simulated concentration. All observed and simulated concentrations were standardized for a lamivudine dose of 80 mg for the BID regimen and 160 mg for the OAD regimen as dose proportionality of lamivudine pharmacokinetics has previously been demonstrated (12). The 5th, 50th and 95th percentiles of the simulated concentrations at each time were then overlaid on the observed concentration data, and a visual inspection was performed. The variability was reasonably estimated if the 95% confidence interval (95% CI) for the proportion of observed data outside the bounds included the theoretical value of 10%.

The theoretical dose needed to reach the range of 24 h of exposure in adults observed from previous studies (from 8.9 to 16.6 mg·h/liter) (7, 24) of the function of age in weeks and body weight (for the older patients) was calculated from our model.

Recommended doses were then derived and simulated in each group, the area under the concentration-time curve from 0 to 24 h (AUC_{0–24}) values obtained from the simulations were compared to the range of the previously described values for AUC_{0–24} in adults obtained following an administration of 300 mg of lamivudine OAD (7, 24).

A total of 580 patients and 2,106 plasma drug concentrations were available for pharmacokinetic evaluation. The mean time of follow-up was 2.5 months.

A total of seven concentrations were below the limit of quantification (BLQ). A two-compartment model adequately described the data (Fig. 1), and thus the apparent parameters of the model were the clearance (CL/*F*), the central volume of distribution (*V _{c}*/

Observed lamivudine concentrations (○) and population predicted lamivudine concentrations (curve) in log scale as a function of time for BID and OAD regimens. Asterisks represent concentrations below the limit of quantification.

Population pharmacokinetic parameters of lamivudine standardized for a body weight of 70 kg by using an allometric model in 580 HIV-1-infected children^{a}

Thus, the final covariate model on the parameters was:

according to the model, the values for PMA_{50} and γ were 59 weeks and 3.02, respectively, where PMA_{50} is the PMA at which clearance reaches 50% of the adult size-adjusted value and γ is the power term for the effect of age on clearance.

Figure 2 displays the variation of clearance (liters/h/70 kg) as a function of age. The apparent elimination clearance increases gradually from birth to the first years of age.

Apparent elimination clearance expressed in liters/h/70 kg (○) as a function of age. The line represents the equation defined by the model.

The galenic form had no significant effect.

Table 2 displays the AUC_{0–24} minimum and maximum concentrations (*C*_{min} and *C*_{max}, respectively) resulting from the BID and OAD regimens. The OAD *C*_{min} were significantly lower than those observed with the BID regimen: they decreased by 54.5% and 53.3% for children and adolescents, respectively. The OAD *C*_{max} were significantly higher than those observed with the BID regimen: they increased by 72.7% and 58.3% for children and adolescents, respectively. The 24-h exposures were not significantly different in children (*P* = 0.75) and adolescents (*P* = 0.20).

Table 1 summarizes the final population pharmacokinetic estimates. All of the parameters were well estimated, given their percent relative standard error (RSE). The η-shrinkages for CL/*F* and *V _{c}*/

Figure 3 (VPC) shows that the average prediction matches the observed concentration time courses and that the variability is reasonably estimated. The numbers (percentages) of observed points within the 90% prediction interval for every 12 h (q12h) and q24h were 1,639/1,804 (90.8%) and 254/289 (87.8%), respectively.

Figure 4 displays the theoretical dose needed to reach the range of 24 h of exposure observed from previous adult studies (from 8.9 to 16.6 mg·h/liter) (7, 24) as a function of age in weeks and body weight (for the older patients) according to our model. To be closer to adult exposure, the lamivudine doses in children appear to be 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks, 6 mg/kg from 16 to 25 weeks, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg, 225 mg/day from 25 to 35 kg, and 300 mg/day thereafter.

The gray areas represent the doses of lamivudine (mg/kg/24 h) needed to reach the range for the AUC_{0–24} values observed in adults (from 8.9 to 16.6 mg·h/liter) as a function of age (A) and body weight (B). The bold lines represent our **...**

Table 4 displays the simulated AUC_{0–24} obtained with our dosing recommendations in each group. According to follow-up time, a patient can be included in successive groups. From neonates to adolescents, the AUC_{0–24} values obtained were in the range of previously described values in adults. As shown in Fig. 5, AUC_{0–24} values obtained from 400 Monte Carlo simulations with our dosing recommendation were all included in the AUC_{0–24} adult range. However, the AUC_{0–24} values derived from the FDA recommendation led to pediatric exposure over the AUC_{0–24} adult range, especially in the newborns.

Simulated exposures obtained from our recommended lamivudine doses according to age and/or body weight

This article describes lamivudine pharmacokinetics in 580 children from 2 days to 18 years of age. Lamivudine concentrations were satisfactorily described by a two-compartment model. Lamivudine freely penetrates tissue beyond the systemic circulation and is able to distribute through a peripheral compartment (12, 19). The apparent elimination clearance and AUC_{0–24} in each age group were consistent with those in previous studies (Table 3). The apparent elimination clearance (CL/*F* = 31 liters/h/70 kg) was consistent with previous adult studies: 29.6 liters/h (18) and 26.7 liters/h (10). The apparent volume of distribution (central plus peripheral) was consistent with previous adult studies: 205.4 liters/70 kg versus 128 liters (17) and 238 liters (5).

The population model was also used to investigate the effect of growth (body weight) and maturation (age) on pharmacokinetic parameters. In our model, after allometric scaling of the parameters, an effect of age, PMA, on clearance was also observed. The PMA parameters for the clearance, γ and PMA_{50}, are similar to those reported for vancomycin (3). The PMA_{50} found in this study for lamivudine (59 weeks) is greater than the PMA_{50} of 48 weeks reported for maturation of the glomerular filtration rate (GFR) (21). The clearance of 31 liters/h/70 kg for a drug that is 70% eliminated by the kidney and not highly protein bound means that it must be excreted by tubular secretion. The later maturation of lamivudine clearance may suggest that tubular secretion develops later than the GFR. On the other hand, the discrepancy between the rate of maturation of GFR and maturation of lamivudine CL/*F* should be addressed also as follows: older infants may have a lower CL/*F* than the value that could be expected from PMA and weight alone because they would be sicker, having been infected longer with HIV.

According to this model, clearance increases gradually up through the first years of age. This relationship between lamivudine clearance and age was supported by the study by Tremoulet et al. (23), which demonstrated the rapid maturation of renal function occurring from birth and persisting during the subsequent few weeks of life.

The variation in lamivudine clearance could be explained by the progressive maturation of renal function with age and body weight during the first years of life.

No relationship between concentration and efficacy of lamivudine in children has been successfully demonstrated. Thus, we considered the range of AUC_{0–24} values observed in adults from previous studies following administration of 300 mg OAD of lamivudine (7, 24). Considering this range of AUC_{0–24} values, the calculated dose needed to reach this adult exposure according to age shows that the transition from 4 mg/kg/day to 8 mg/kg/day at 6 weeks of age (FDA recommendation) should be reconsidered. Our simulations show that a dosing scheme gradually increasing the dose (mg/kg) according to weeks of age seems to maintain exposure closer to that in the adult and better reflects the maturation of renal function occurring from birth and persisting during the first weeks of life.

The actual FDA recommendations for lamivudine in older children (150 mg/day from 14 to 21 kg of body weight, 225 mg/day from 21 to 30 kg, and 300 mg/day thereafter) are close to our recommendations. In conclusion, this study reports lamivudine pharmacokinetics in children ranging from neonates to adolescents. The pharmacokinetic parameters were consistent with those from previous studies. The lamivudine elimination clearance is related to the maturation of renal function and varies as a function of age and body weight. Moreover, this modeling reflects fully mature adult values. According to simulations, to be closer to adult exposure, children should receive the following lamivudine doses: 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.

We acknowledge the Pediatric European Network Treatment AIDS Laboratory Network (PENTA-LABNET) for financial support.

^{}Published ahead of print on 16 May 2011.

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