Developmental Pharmacokinetics of Lamivudine in 580 Pediatric Patients Ranging from Neonates to Adolescents

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2011, p Vol. 55, No /11/$12.00 doi: /aac Copyright 2011, American Society for Microbiology. All Rights Reserved. Developmental Pharmacokinetics of Lamivudine in 580 Pediatric Patients Ranging from Neonates to Adolescents 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 EA 3620, Université Paris Descartes, Paris, France 1 ; Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, France 2 ; Service de Pharmacologie Clinique, AP-HP, Hôpital Cochin-Saint-Vincent-de-Paul, 3 CIC-0901 Inserm, Cochin-Necker, 4 Paris, France; and Unité d Immunologie Hématologie Pédiatrique, Hôpital Necker Enfants Malades, AP-HP, Paris, France 5 Received 22 November 2010/Returned for modification 16 April 2011/Accepted 28 April 2011 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 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 h 1, respectively. According to the model, elimination clearance (liters/h/ 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 %) 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 * Corresponding author. Mailing address: Unité de Recherche Clinique, Hôpital Tarnier, 89 Rue d Assas, Paris, France. Phone: Fax: naim.bouazza@cch.aphp.fr. Published ahead of print on 16 May determine the relationship between lamivudine pharmacokinetics and age or body weight and to investigate the consistency of the current recommended pediatric dosage regimen. MATERIALS AND METHODS Patients and treatment. 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-tochild 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. Analytical method. Lamivudine was measured in a 100 l 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 2 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%. Modeling strategy and population pharmacokinetic model. Data were analyzed using the nonlinear mixed effect modeling software program Monolix, version 31s ( (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 [ ]) were ascribed to an exponential model. Parameter shrinkage was calculated as {1 SD( )/ }, where SD( ) and are the standard deviation of individual pa- 3498

2 VOL. 55, 2011 LAMIVUDINE POPULATION PHARMACOKINETICS IN CHILDREN 3499 FIG. 1. Observed lamivudine concentrations (E) 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. rameters 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 P STD (BW i /BW STD ) PWR, where P STD is the standard value of parameter for a patient with the standard body weight (BW STD ) value and P i and BW i are the parameter and body weight, respectively, of the ith individual. The PWR (power) exponents may be estimated from the data. However, from allometric scaling theory these are typically 0.75 for clearance parameters and 1 for volumes of distribution (2). 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 CL 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. Visual predictive check (VPC) validation. 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%. Dose simulations. 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). RESULTS Demographic data. 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. Population pharmacokinetics. A total of seven concentrations were below the limit of quantification (BLQ). A twocompartment 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 /F), the peripheral volume of distribution (V p /F), the intercompartmental clearance (Q/F), and the absorption rate constant (K a ) (Table 1). F is the unknown bioavailability. The proportional plus additive error model displayed a nonsignificant additive part, and thus residual variability was described by a proportional error model. Intersubject variability was described by the exponential error model and retained only for apparent clearance and central volume of distribution. Samples were obtained at different occasions; the number of samples per occasion was 1 and did not allow estimation of interoccasion variability. The allometric scaling of clearance (CL and Q) and volume (V c and V p ) terms improved the goodness of fit. After the inclusion of the allometric scaling, age also had a significant effect on clearance. Thus, the final covariate model on the parameters was:

3 3500 BOUAZZA ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Population pharmacokinetic parameters of lamivudine standardized for a body weight of kg by using an allometric model in 580 HIV-1-infected children a Parameter Mean RSE (%) Structural model K a (h 1 ) CL/F (liters/h) 31 2 V c /F (liters) Q/F (liters/h) V p /F (liters) PMA 50 (wk) 59 4 Statistical model CL/F Vc /F (proportional) a RSE, relative standard error (standard error of estimate/estimate 100); K a, absorption rate constant; CL/F, apparent elimination clearance; V c /F, apparent central volume of distribution; V p /F, apparent peripheral volume of distribution; Q/F, intercompartmental clearance;, proportional residual variability estimate;, interindividual variability estimates;, power term for the effect of age on clearance; PMA 50, PMA at which clearance reaches 50% of the adult sizeadjusted value. The typical parameters refer to an adult patient weighing kg according to the allometric model value typical parameter (body weight/ ) PWR, where PWR 0.75 for the CL and Q terms and 1 for the V c and V p terms. This value is multiplied by the PMA effect, PMA /(PMA PMA 50 ), for CL/F. CL/F CL BW 0.75 PMA 50 V C /F Vc BW PMA PMA Q/F Q BW 0.75 V p /F Vp BW according to the model, the values for PMA 50 and 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 is the power term for the effect of age on clearance. Figure 2 displays the variation of clearance (liters/h/ kg) as a function of age. The apparent elimination clearance increases gradually from birth to the first years of age. 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 -shrinkages for CL/F and V c /F were 0.19 and 0.39, respectively, indicating that the empirical Bayesian estimates for individual parameters are reliable for clearance but not for volume of distribution, which had a shrinkage value greater than Downloaded from on May 14, 2018 by guest FIG. 2. Apparent elimination clearance expressed in liters/h/ kg (E) as a function of age. The line represents the equation defined by the model.

4 VOL. 55, 2011 LAMIVUDINE POPULATION PHARMACOKINETICS IN CHILDREN 3501 Parameter TABLE 2. Comparison of pharmacokinetic parameters obtained from BID and OAD regimens Children (1 11 yr old) (n 302) BID (4 mg/kg q12h) OAD (8 mg/kg q24h) Median (SD) result for dose regimen shown: P value (ANOVA) Adolescents ( 12 yr old) (n 114) BID (150 mg q12h) OAD (300 mg q24h) P value (ANOVA) AUC 0 24 (mg h/liter) 12.5 (4.0) 11.1 (3.8) (3.8) 12.8 (3.6) 0.20 C min (mg/liter) 0.11 (0.12) 0.05 (0.11) (0.09) 0.07 (0.06) 10 4 C max (mg/liter) 1.1 (0.23) 1.9 (0.47) (0.32) 1.9 (0.44) % (13). However, doses were simulated in order to achieve a target AUC. The estimation of individual AUC is only based on individual clearance. Table 3 summarizes lamivudine AUC 0 24 and CL/F in the present and previous studies for different age groups. Evaluation and validation. 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. Dose simulations. 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. 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. DISCUSSION 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/ 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: liters/ 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 TABLE 3. Comparison of lamivudine derived pharmacokinetic parameters CL/F and AUC 0 24 between our study and the latest publications on HIV-1-infected children according to age group Age group (n) Median (SD) daily dose (mg/kg) CL (liters/h/kg) Median (95% CI) AUC 0 24 (mg h/liter) Source or reference Newborns 1 mo (77) 4 (7.2) 0.26 ( ) 16.7 ( ) This study 3 28 days (40) ( ) 12.0 ( ) 23 1 day (16) ( ) 19.6 ( ) 16 7 days (16) ( ) 15.8 (14 18) 16 Infants 1 yr (45) 7 (5.2) 0.49 ( ) 13.0 ( ) This study 29 days to 3 yr (59) ( ) 13.6 ( ) 23 Children 1 11 yr (426) 7.7 (2.6) 0.64 ( ) 12.2 ( ) This study 2 13 yr (19) ( ) 8.9 ( ) yr (17) ( ) 7.4 ( ) 8 Adolescents yr (129) 6.7 (2.5) 0.49 ( ) 13.1 ( ) This study 7 18 yr (34) ( ) 13.0 ( ) 8

5 3502 BOUAZZA ET AL. ANTIMICROB. AGENTS CHEMOTHER. FIG. 3. Evaluation of the final model: comparison between the 95% confidence intervals (95% CI) of the 5th, 50th, and 95th percentiles obtained from 1,000 simulations (lines) and the percentiles calculated from the observations for lamivudine concentrations standardized for lamivudine doses of 80 mg and 160 mg, respectively, for the BID (A) and OAD (B) regimens. the parameters, an effect of age, PMA, on clearance was also observed. The PMA parameters for the clearance, 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/ kg for a drug that is % 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 FIG. 4. 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 dosing recommendations.

6 VOL. 55, 2011 LAMIVUDINE POPULATION PHARMACOKINETICS IN CHILDREN 3503 TABLE 4. Simulated exposures obtained from our recommended lamivudine doses according to age and/or body weight Group by age and/or body wt (n) Total daily dose Median (SD) AUC 0 24 (mg h/liter) a 8 wk (82) 4 mg/kg 13.4 (6.2) 8 16 wk (13) 5 mg/kg 12.1 (4.8) wk (17) 6 mg/kg 12.2 (6) 25 wk to 14 kg (113) 8 mg/kg 12.2 (5.6) kg (241) 150 mg 12.3 (5.1) kg (192) 225 mg 14.1 (5.9) 35 kg (149) 300 mg 13.8 (5.5) a For comparison, the adult range of AUC 0 24 values was 8.9 to 16.6 mg h/ liter (7, 24). 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 Downloaded from on May 14, 2018 by guest FIG. 5. Median AUC 0 24 obtained from 400 Monte Carlo simulations with our dose recommendation and from the FDA recommendation as a function of age and body weight. The gray areas represent the ranges for AUC 0 24 observed in adults (from 8.9 to 16.6 mg h/liter). Asterisks correspond to AUC 0 24 values outside the adult range.

7 3504 BOUAZZA ET AL. ANTIMICROB. AGENTS CHEMOTHER. 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. ACKNOWLEDGMENT We acknowledge the Pediatric European Network Treatment AIDS Laboratory Network (PENTA-LABNET) for financial support. REFERENCES 1. Reference deleted. 2. Anderson, B. J., and N. H. G. Holford Mechanism-based concepts of size and maturity in pharmacokinetics. Annu. Rev. Pharmacol. Toxicol. 48: Anderson, B. J., K. Allegaert, J. N. Van den Anker, V. Cossey, and N. H. Holford Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br. J. Clin. Pharmacol. 63: Reference deleted. 5. Benaboud, S., et al Pregnancy-related effects on 3TC pharmacokinetics: a population study with 228 women, abstr th Conf. Retrovir. Opportunistic Infect. 6. Bergshoeff, A., et al Plasma pharmacokinetics of once- versus twicedaily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir. Ther. 10: Bruno, R., et al Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV. Clin. Pharmacokinet. 40: Burger, D. M., et al Age-dependent pharmacokinetics of lamivudine in HIV-infected children. Clin. Pharmacol. Ther. 81: Chen, N., K. Aleska, C. Woodland, M. Rieder, and G. Koren Ontogeny of drug elimination by the human kidney. Pediatr. Nephrol. 21: Heald, A. E., et al Pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with renal dysfunction. Antimicrob. Agents Chemother. 40: Ihaka, R., and R. Gentleman R: a language for data analysis and graphics. J. Comput. Graph. Stat. 5: Johnson, M. A., K. H. Moore, G. J. Yuen, A. Bye, and G. E. Pakes Clinical pharmacokinetics of lamivudine. Clin. Pharmacokinet. 36: Karlsson, M. O., and R. M. Savic Diagnosing model diagnostics. Clin. Pharmacol. Ther. 82: Kuhn, E., and M. Lavielle Maximum likelihood estimation in nonlinear mixed effects models. Comput. Stat. Data Anal. 49: Reference deleted. 16. Moodley, D., et al Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. J. Clin. Pharmacol. 41: Moore, K. H., et al Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials. Antimicrob. Agents Chemother. 43: Moore, K. H., et al Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin. Pharmacol. Ther. 59: Mueller, B. U., et al Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. Antimicrob. Agents Chemother. 42: Pinheiro, J. C., and D. M. Bates Mixed-effects models in S and S-PLUS. Springer Verlag, New York, NY. 21. Rhodin, M. M., et al Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr. Nephrol. 24: Savic, R. M., and M. O. Karlson Shrinkage in empirical Bayes estimates for diagnostics and estimation. Population Approach Group Europe, Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 23. Tremoulet, A. H., et al Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants. Antimicrob. Agents Chemother. 51: ViiV Healthcare UK, Ltd. 25 October 2010, posting date. Epivir, summary of product characteristics. ViiV Healthcare UK, Ltd., Uxbridge, Middlesex, United Kingdom. Downloaded from on May 14, 2018 by guest