Population pharmacokinetics of tenofovir in AIDS patients

The interindividual variability of tenofovir pharmacokinetics in HIV+ patients is quite large, but the sources of variability are incompletely understood. Intraindividual variability has not been characterized, although it may have an impact on efficacy and therapeutic drug monitoring. The aims of the study were to estimate intraindividual variability of tenofovir clearance and to assess interactions with associated antiviral drugs. Tenofovir concentrations (median 2; range, 1-5) were measured in 175 patients during several dosing intervals. Covariates and dosing regimen of associated antiretroviral drugs were recorded prospectively. The data were analyzed by a population approach. The final model was a 2-compartment model with first-order absorption rate. The elimination clearance was found to be related to the ratio of body weight to serum creatinine. Among the 15 drugs coadministered, no interaction on tenofovir kinetics was significant. The global variability of CL/F, after accounting for variability to variation of body weight and serum creatinine, was about 50%, with 20% due to interindividual variability and 30% due to interoccasion variability. In a few patients, clearance (and AUC) could vary by a factor of 2 between occasions. The interoccasion variability was not related to the delay between occasions. In the context of drug monitoring, for a given patient, the dose should not be adapted unless the variation of concentration between 2 occasions is large, or the 24-hour trough concentration at steady state is lower than 12 microg/L.     

The utility of mixed-effects covariate analysis in rapid selection of doses in pediatric subjects: a case study with fexofenadine hydrochloride

Fexofenadine hydrochloride is a non-sedating antihistamine that is used in the treatment of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. A pooled analysis of pharmacokinetic data from children 6 months to 12 years of age and adults was conducted to identify the dose(s) in children that produce exposures comparable to those in adults for the treatment of seasonal allergic rhinitis. The pharmacokinetic parameter database included peak and overall exposure data from 269 treatment exposures from 136 adult subjects, and 90 treatment exposures from 77 pediatric allergic rhinitis patients. The data were pooled and analysed using NONMEM software, version 5.0. A covariate model based on body weight and age and a power function model based on body weight were identified as appropriate models to describe the variability in fexofenadine oral clearance and peak concentration, respectively. Individual oral clearance estimates were on average 44%, 36% and 61% lower in children 6 to 12 years (n=14), 2 to 5 years (n=21), and 6 months to 2 years (n=42), respectively, compared with adults. Trial simulations (n=100) were carried out based on the final pharmacostatistical models and parameter estimates to identify the appropriate dose(s) in children relative to the marketed dose of 60 mg fexofenadine hydrochloride in adults. The trials were designed as crossover studies in 18 subjects comprising various potential dosing regimens with and without weight stratification. Pharmacokinetic parameter variability was assumed to have a log-normal distribution. Individual weights and ages were simulated using mean (SD) estimates derived from the studies used in this analysis and proportional measurement/model mis-specification errors derived from the analysis were incorporated into the simulation. The results indicated that a 30 mg dose of fexofenadine hydrochloride administered to children 1 to 12 years of age and weighing >10.5 kg and a 15 mg dose administered to children 6 months and older and weighing 相似文献   

Pharmacokinetic prediction for intravenous beta-lactam antibiotics in pediatric patients

A method for predicting pharmacokinetics in pediatric patients for intravenous beta-lactam antibiotics is proposed. We focused on the allometric relationships of pharmacokinetic parameters with individual body weights (BW) in human including healthy adults and pediatric patients. Drug concentration data for 15 intravenous beta-lactam antibiotics were collected retrospectively from the published articles and the individual pharmacokinetic parameters were re-calculated. A mixed effect modeling (MEM) was applied for the allometric relationship for those beta-lactam antibiotics, and mean and variances of inter-drug variability for the allometric parameters and also variance for intra-drug (residual) variability were estimated. Then drug-specific allometric parameters were estimated by an empirical Bayesian method using the pharmacokinetic parameters for a drug only in healthy adults as observations, and finally the individual pharmacokinetic parameters in pediatric patients were predicted. The predictability of the method was evaluated by the leave-one-out method. We also demonstrated a method for simulating plasma concentration-time profiles in pediatric patients, and the predicted time-course curves generally coincided well with the actual plasma concentration data for the tested drugs.     

The value of relative organ weights

It is accepted practice in presenting organ weight data to express the results relative to the animal's body weight. The data presented suggest that in rats no benefits are obtained from this method either in reducing the variability of the data or in removing bias due to different body weights. By using simulated data it is further shown that relative weights can lead to erroneous conclusions and misinterpretation of drug effects and it is concluded that workers should present their results in absolute as opposed to relative weights.     

替诺福韦治疗艾滋病导致的范可尼综合征回顾性分析

目的:分析替诺福韦(TDF)治疗艾滋病导致的范可尼综合征(FS)的影响因素和预后。方法:对2014年1月-2016年9月发生的64例TDF相关的FS进行统计、分析。结果:FS发生率为2.08%,大部分在使用TDF 2~4年内发生,主要表现为电解质紊乱、尿蛋白和尿糖高,51.56%的患者合并肾小球滤过率下降,37.50%的患者合并骨质疏松。FS好发人群以年龄大、体质量低和合并有基础疾病为主。停用TDF和对症治疗后大部分好转,4例经过1年治疗无缓解。结论:使用TDF要定期监测肾功能、尿常规和电解质,发现FS要及时治疗。     

Variability in the uterotrophic response assay (an in vivo estrogenic response assay) in untreated control and positive control (DES-DP, 2.5 microG/kg, bid) Wistar and Sprague-Dawley rats

Inclusion of biological outlier values was found to bias the results of rat uterotrophic assays towards false negatives, i.e., not identify uterotrophic effects in treated populations. The present investigation was conducted to identify the background variability in the rat uterotrophic assay and to evaluate the need to exclude biological outlier values in untreated control groups. The Styrene Steering Committee (SSC) of the European Chemical Industry Council (CEFIC) co-sponsored this work with Argus Research Laboratories (Argus). The rat uterotrophic response assay originally was used as a pharmacology screen to identify estrogenic agents. Classically, 5 to 10 immature female rats (18 to 22 days of age) are administered an agent for three or four days. At sacrifice on the following day (21 to 26 days of age), the uterus is removed, weighed and a uterine weight/terminal body weight ratio calculated. This in vivo assay has been adapted for use in identifying the potential estrogenicity of chemicals, generally using 10 immature female rats per group, more closely controlling the ages, and adding one or more positive control groups to demonstrate sensitivity and response of the test system. Statistically significant increases in the positive control group means for absolute and relative uterine weights, as compared with the untreated (or vehicle-treated) means, is generally interpreted as identifying a sensitive test system. The untreated (and/or vehicle-treated) control group is then compared with the various test groups, and statistically significant increases in the mean absolute and relative uterine weights are identified as evidence of estrogenicity of the agent. Although not fully described previously, the inherent biological variability existing in both untreated and treated animals, can confound interpretation of the data, especially when numbers are relatively small. Our laboratories have identified that under controlled GLP-compliant conditions, some Wistar rats [randomly assigned (weight-ordered) to groups of ten at 22 +/- 1 days of age, and sacrificed when 26 +/- 1 days of age] in untreated control groups have high relative uterine weights that skew data distributions such that statistically significant differences are not present between untreated control and positive control groups. Based on these observations, further evaluations of untreated control and positive control (DES-DP, 2.5 micrograms/kg, b.i.d.) populations of three rat strains [Wistar--Chbb:THOM-SPF, Wistar--Crl:(WI)BR and Sprague-Dawley--Crl:CD(SD)IBS BR VAF/Plus "International Genetic Standard"] were made to define when such normal findings should be considered biological outliers, and whether outlier values should be excluded from analyses. Our data indicate that body weight is not always predictive of uterine weight, that relative uterine weight outlier values occur in each of these rat strains, and that statistically significant differences exist between groups of untreated control animals when outlier values are included in analyses. Of 98, 60 and 60 untreated control rats in the three respective strains, 11 (11.2%), 16 (26.7%) and 15 (25.0%) had relative uterine weights > or = 0.150%, and 5 (5.1%), 4 (6.7%) and 9 (15.0%) of these rats had relative uterine weights > or = 0.200%, values within the positive control range. All positive control rats attained relative uterine weights > or = 0.100%. Of 50, 60 and 60 positive control rats in the three respective rat strains, 27 (54%), 47 (78.3%) and 36 (60%) had relative uterine weights > or = 0.200%, 9 (18%), 2 (3.3%) and 7 (11.7%) had relative uterine weights > or = 0.300% and 5 (10%), 1 (1.7%) and 3 (5%) had relative uterine weights > or = 0.400%. The incidences of relative uterine weights > or = 0.300% in the positive control group may indicate the presence of high responders. Histological evaluations of uteri of positive control rats and untreated control rats with relative uterine weights > or = 0.     

Organ weights and fat volume in rats as a function of strain and age

The Fischer 344 (F344) rat and the Sprague-Dawley (SD) rat are used commonly to evaluate potential adverse health effects resulting from environmental exposure to chemicals. They are also the most common rat strain/stock used in physiologically based pharmacokinetic (PBPK) modeling. Accurate characterization of model input parameters will improve the usefulness of PBPK model predictions. Thus, organ (i.e., liver, kidneys, spleen, stomach, small intestine, large intestine, heart, lungs, brain) weights and body fat were measured in male SD rats of different ages (4 to 40 wk) and in young (9 to 10 wk) and old (22 to 23 mo) male F344 rats. Comparison of age-matched (9 to 10 wk) F344 and SD rats revealed that the SD rats weighed significantly more and had significantly higher absolute organ weights. These significant differences usually disappeared when organ weights were expressed as a percentage of body weight (relative organ weight). Percent body fat was significantly lower in the age-matched SD rats (6.48%) than in their F344 counterparts (8.67%). As expected, both body weight and absolute organ weights were significantly higher in old than in young F344 rats. However, these differences were largely reversed when relative organ weights were considered, with most relative organ weights significantly lower in the old F344 rats. Body fat as a percentage of body weight was 14.02% in the old F344 rats. When SD rats of various ages were examined, relative organ weights declined between the ages of 4 and 14 wk. In contrast, significant differences in percent body fat were not detected among the SD rats of different ages and weights examined in this study (4 to 40 wk, approximately 75 to approximately 450 g). In summary, values for physiological input parameters are provided that should prove useful in development and implementation of more accurate PBPK models.     

Predictive Performance of a Busulfan Pharmacokinetic Model in Children and Young Adults

BACKGROUND:: Recently a pediatric pharmacokinetic (PK) model was developed for busulfan to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation in terms of toxicity and event free survival. This study assesses the predictive performance of this busulfan PK model in a new, more diverse pediatric population, including data from patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices, from 5 international pediatric transplant centers. PATIENTS AND METHODS:: The previously published (original) busulfan PK model was developed from data of 245 patients (0.1-26 years of age). To externally validate this model, data were collected from another 158 patients (0.1-35 years) who underwent hematopoietic stem cell transplantation in 5 international transplant centers. Observed versus predicted plots, normalized prediction distribution error analysis, refit of the model on the external (n = 158) and combined datasets (n = 403), and subpopulation analyses were evaluated. RESULTS:: The original busulfan PK model was found to be stable and parameter estimates precise. Concentrations predicted by this model were in good agreement with the observed concentrations from the 5 external datasets. Plasma concentrations in patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices were adequately predicted. CONCLUSIONS:: Our pediatric busulfan PK model has been externally validated. This model predicts busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight age, or body mass index. This busulfan PK model forms the basis for individualized busulfan dosing.     

Estimating degradation in real time and accelerated stability tests with random lot-to-lot variation: a simulation study

The effect of different lot-to-lot variability levels on the prediction of stability are studied based on two statistical models for estimating degradation in real time and accelerated stability tests. Lot-to-lot variability is considered as random in both models, and is attributed to two sources-variability at time zero, and variability of degradation rate. Real-time stability tests are modeled as a function of time while accelerated stability tests as a function of time and temperatures. Several data sets were simulated, and a maximum likelihood approach was used for estimation. The 95% confidence intervals for the degradation rate depend on the amount of lot-to-lot variability. When lot-to-lot degradation rate variability is relatively large (CV > or = 8%) the estimated confidence intervals do not represent the trend for individual lots. In such cases it is recommended to analyze each lot individually.     

Statistical evaluation of physiological variability of rifampicin in fixed dose combinations

Tuberculosis is one of the microbial diseases having a long history of its occurrence and yet to be eradicated from the world. Due to the development of bacterial resistance, treatment has changed from monotherapy to combotherapy to fixed dose combinations (FDCs). Rifampicin has been found one of the most important anti-tubercular drugs, however variable bioavailability of rifampicin in some FDCs as well as separate formulations has been reported in the literature, and led to the development of WHO model protocol for evaluation of FDCs for bioequivalence trials. In present investigation, role of physiological variability in rifampicin bioequivalence was studied. Influence of subject's body weight, inter/intra-individual variability of elimination rate and impact of outliers on the decision of bioequivalence were investigated. Normalization of pharmacokinetic measures for bioequivalence (AUC and C(max)) were carried out as per body weights and elimination rate constants of subjects, then different statistical tests like two-way ANOVA, hauschke analysis, normal and log-transformed confidence interval were applied to check for the change in bioequivalence decision. It was found that normalization as per body weights did not play a significant role in the outcome of bioequivalence endpoint. Similarly, elimination rate variability and outliers have been found insignificant regarding final outcome of bioequivalence study. Hence, it has been concluded that physiological variability did not play a significant role in bioequivalence of rifampicin in FDCs.     

86例HIV感染患者的肾功能状态与危险因素分析

目的：分析HIV患者肾功能状态与危险因素,深化对该人群肾损害风险的认识。方法收集HIV患者临床资料,包含年龄、性别、高血压和糖尿病病史、感染途径、抗逆转录病毒治疗（ ART）等,检测血常规,完善外周血CD4淋巴细胞计数、乙肝表面抗原定性、抗丙型肝炎病毒抗体定性和HIV?RNA定量分析,运用血肌酐值估算肾小球滤过率（ eGFR）,Logistic回归分析各因素与肾功能状态的相关关系。结果86例黑人HIV患者,女性20例（23．3％）,年龄（45．3±10．7）岁,eGFR水平（74．9±23．4）mL／（min·1．73m2）。肾功能损害25例,肾功能正常61例。肾功能损害组患者年龄、高血压与糖尿病比例、WHO临床分期和基线HIV?RNA定量均显著高于肾功能正常组患者,而Hb、入院CD4淋巴细胞计数和eGFR水平均显著低于肾功能正常组患者（P均＜0．05）。肾功能正常组含替诺福韦（TDF）方案的患者eGFR水平显著低于未含 TDF方案的患者（P＜0．05）。多因素Logistic回归分析显示HIV患者肾功能损害的独立相关因素为年龄≥50岁、合并糖尿病和WHO临床分期。结论除传统危险因素外,HIV感染及某些ART药物均可能与HIV患者肾功能损害有关。     

Determinants of increased drug self-administration due to food deprivation

Changes in oral etonitazene self-administration were compared in four groups of rats that were maintained at 100, 95, 85, or 75% of their pre-experimental free-feeding body weights. Etonitazene (5 g/ml) or water was available for 16 h according to a fixed-ratio (FR) 1 schedule. Each liquid delivery (0.1 ml) was contingent upon a lever-press response. During food deprivation etonitazene intake gradually increased to over two-fold as body weights decreased over 25 sessions; etonitazene intake was inversely proportional to body weight. The 75% weight group showed stereotypy, self-mutilation and large variability in daily etonitazene intake. In another experiment a range of deprivation conditions was studied in a group of six rats with etonitazene (5 g/ml) or water available on an FR 8 schedule during 1-h sessions. When the rats were gradually food satiated, etonitazene-maintained behavior declined but remained higher than water-maintained behavior; however, when they were abruptly food satiated, etonitazene-maintained behavior decreased to low levels.     

Tenofovir induced Fanconi syndrome: A possible pharmacokinetic interaction

Tenofovir was introduced as a second line drug for the treatment of human immunodeficiency virus (HIV) infection in India in December 2009. Although rare, renal toxicity is a recognized adverse drug reaction (ADR) of this drug, especially when administered with boosted lopinavir-ritonavir. In this case, an HIV positive patient receiving tenofovir based antiretroviral therapy (ART) for last 1 year developed albuminuria, glycosuria and hypophosphatemia. Renal function tests and random blood sugar were within normal limits. He was diagnosed as a case of tenofovir induced Fanconi syndrome. Tenofovir was discontinued and patient was prescribed an alternate regimen. Five months later clinical symptoms and renal functions returned to normal. A pharmacokinetic interaction between tenofovir and ritonavir may have resulted in the toxicity. A periodic monitoring of renal functions is desirable in patients on tenofovir based ART.KEY WORDS: Adverse drug reaction, Fanconi syndrome, protease inhibitor, tenofovir     

Safety and pharmacokinetics of oral lansoprazole in preadolescent rats exposed from weaning through sexual maturity

Proton pump inhibitors, the reference standard in adults with acid-related disorders, are increasingly being used in children despite limited pediatric safety and pharmacokinetic data. This study evaluated these parameters in rats aged 21-60 days, which approximately correlates with children aged 2-11 years. Lansoprazole at doses of 0, 5, 15, 50, or 150 mg/kg per day was administered to Sprague-Dawley rats from weaning through sexual maturity. Safety assessments included clinical, neurobehavioral, ophthalmologic, and gender-specific developmental milestones, clinical pathology including urinalysis, organ weight (at necropsy), and histopathologic evaluation. Blood samples for pharmacokinetics were collected on the first and last days of treatment. After the end of dosing, decreases in body weight gain, serum total protein and albumin (males), and microcytic hypochromic anemia were observed at doses of > or =50mg/kg per day, and hypoglycaemia (females) at 150 mg/kg per day. Selected groups exhibited increases in absolute and relative duodenal and stomach weights (> or =15 mg/kg per day), decreases in absolute and relative thymus weights (> or =50 mg/kg per day), increased relative liver weights (> or =50 mg/kg per day), and chronic adhesions to the spleen (> or =15 mg/kg per day). No other changes were observed. The area under the curve values in 60-day-old rats was less than those observed in 21-day-old rats. Areas under the curve values for lansoprazole were higher in female than male 60-day-old rats. No unexpected signs of toxicity were observed in the current preadolescent rats relative to those observed in adult rats in previous studies. The NOEL in preadolescent rats was similar to adults and gives a safety margin of one- to five-fold relative to the pediatric dose (0.87 mg/kg in 2-11-year-olds). These results provide comparative evidence for the value of studies in rats to support safety in a pediatric population.     

Application of the Modified Chi-Square Ratio Statistic in a Stepwise Procedure for Cascade Impactor Equivalence Testing

Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low-deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9698-0) contains supplementary material, which is available to authorized users.KEY Words: aerodynamic particle size distribution, bioequivalence, cascade impactor, chi-square ratio statistic, orally inhaled drug products     

Tenofovir primes rhesus macaque cells in vitro for enhanced interleukin-12 secretion

We investigated if the antiviral drug tenofovir has immunomodulatory effects in macaques, similar to those described in murine models. While in vivo experiments were complicated by high individual and temporal variability of immune parameters, tenofovir primed macaque peripheral blood mononuclear cells in vitro for enhanced IL-12 secretion following exposure to bacterial antigens.     

Limited sampling strategy using Bayesian estimation for estimating individual exposure of the once-daily prolonged-release formulation of tacrolimus in kidney transplant children

Background

A limited sampling strategy (LSS) for estimating the area under the curve (AUC) of the prolonged-release formulation of tacrolimus (tacrolimus^PR) is not available in pediatric patients, although the method is of real benefit to children. The objective of this study was to develop and validate a reliable and clinically applicable LSS using Bayesian estimation for estimating tacrolimus^PR AUC in pediatric kidney transplant patients

Methods

The original tacrolimus pharmacokinetic dataset consisted of 22 full profiles from 22 pediatric kidney transplant patients. The Bayesian estimation method was used to develop the LSS. External validation was performed in an independent validation group which consisted of 20 full pharmacokinetic profiles from 12 pediatric kidney transplant patients.

Results

Bayesian estimator using C_0h C_2h and C_3h gave the best predictive performance with a mean prediction error of 2.2 % in the external validation dataset. There was no correlation between the prediction error and age. The Bland–Altman analysis showed that the mean difference between the reference and Bayesian-estimated AUC_0-24 was 3.5 (95 % confidence interval ?3.5–10.5) ng h/mL

Conclusions

A reliable and clinically applicable LSS for estimating AUC_0–24 of tacrolimus^PR was determined and validated in children. The prediction was unbiased and precise. It can be used as a routine procedure to perform AUC-based tacrolimus^PR dosage optimization in pediatric renal transplant patients.     

Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients

Aim

Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates.

Methods

A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine.

Results

The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h^–1, 17.4 l, 2.24 h⁻¹, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis.

Conclusions

A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients.