Model-informed dose optimization of mycophenolic acid in pediatric kidney transplant patients.

PURPOSE: We aimed to develop and evaluate a population PK model of mycophenolic acid (MPA) in pediatric kidney transplant patients to aid MPA dose optimization. METHODS: Data were collected from pediatric kidney transplant recipients from a Dutch academic hospital (Radboudumc, the Netherlands). Pharmacokinetic model-building and model-validation analyses were performed using NONMEM. Subsequently, we externally evaluated the final model using data from another academic hospital. The final model was used to develop an optimized dosing regimen. RESULTS: Thirty pediatric patients were included of whom 266 measured MPA plasma concentrations, including 20 full pharmacokinetic (PK) curves and 24 limited sampling curves, were available. A two-compartment model with a transition compartment for Erlang-type absorption best described the data. The final population PK parameter estimates were Ktr (1.48 h-1; 95% CI, 1.15-1.84), CL/F (16.0 L h-1; 95% CI, 10.3-20.4), Vc/F (24.9 L; 95% CI, 93.0-6.71E25), Vp/F (1590 L; 95% CI, 651-2994), and Q/F (36.2 L h-1; 95% CI, 9.63-74.7). The performance of the PK model in the external population was adequate. An optimized initial dose scheme based on bodyweight was developed. With the licensed initial dose, 35% of patients were predicted to achieve the target AUC, compared to 42% using the optimized scheme. CONCLUSION: We have successfully developed a pharmacokinetic model for MPA in pediatric renal transplant patients. The optimized dosing regimen is expected to result in better target attainment early in treatment. It can be used in combination with model-informed follow-up dosing to further individualize the dose when PK samples become available.

A population pharmacokinetics model of balovaptan to support dose selection in adult and pediatric populations.

Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.

Go beyond the limits of genetic algorithm in daily covariate selection practice.

Covariate identification is an important step in the development of a population pharmacokinetic/pharmacodynamic model. Among the different available approaches, the stepwise covariate model (SCM) is the most used. However, SCM is based on a local search strategy, in which the model-building process iteratively tests the addition or elimination of a single covariate at a time given all the others. This introduces a heuristic to limit the searching space and then the computational complexity, but, at the same time, can lead to a suboptimal solution. The application of genetic algorithms (GAs) for covariate selection has been proposed as a possible solution to overcome these limitations. However, their actual use during model building is limited by the extremely high computational costs and convergence issues, both related to the number of models being tested. In this paper, we proposed a new GA for covariate selection to address these challenges. The GA was first developed on a simulated case study where the heuristics introduced to overcome the limitations affecting currently available GA approaches resulted able to limit the selection of redundant covariates, increase replicability of results and reduce convergence times. Then, we tested the proposed GA on a real-world problem related to remifentanil. It obtained good results both in terms of selected covariates and fitness optimization, outperforming the SCM.

Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis.

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc values were <10 ms at the simulated maximum concentration (Cmax) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

Population Pharmacokinetic-Pharmacodynamic Model of Oxfendazole in Healthy Adults in a Multiple Ascending Dose and Food Effect Study and Target Attainment Analysis.

Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics, and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a life span indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg of body weight once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.

Population pharmacokinetic model selection assisted by machine learning.

A fit-for-purpose structural and statistical model is the first major requirement in population pharmacometric model development. In this manuscript we discuss how this complex and computationally intensive task could benefit from supervised machine learning algorithms. We compared the classical pharmacometric approach with two machine learning methods, genetic algorithm and neural networks, in different scenarios based on simulated pharmacokinetic data. Genetic algorithm performance was assessed using a fitness function based on log-likelihood, whilst neural networks were trained using mean square error or binary cross-entropy loss. Machine learning provided a selection based only on statistical rules and achieved accurate selection. The minimization process of genetic algorithm was successful at allowing the algorithm to select plausible models. Neural network classification tasks achieved the most accurate results. Neural network regression tasks were less precise than neural network classification and genetic algorithm methods. The computational gain obtained by using machine learning was substantial, especially in the case of neural networks. We demonstrated that machine learning methods can greatly increase the efficiency of pharmacokinetic population model selection in case of large datasets or complex models requiring long run-times. Our results suggest that machine learning approaches can achieve a first fast selection of models which can be followed by more conventional pharmacometric approaches.

Population Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending Doses.

Oxfendazole is a potent veterinary benzimidazole anthelmintic under transition to humans for the treatment of multiple parasitic infectious diseases. The first-in-human study evaluating the disposition of oxfendazole and its metabolites in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg of body weight shows that oxfendazole pharmacokinetics is substantially nonlinear, which complicates correlating oxfendazole dose to exposure. To quantitatively capture the relation between oxfendazole dose and exposure, a population pharmacokinetic model for oxfendazole and its metabolites, oxfendazole sulfone and fenbendazole, in humans was developed using a nonlinear mixed-effect modeling approach. Our final model incorporated mechanistic characterization of dose-limited bioavailability as well as different oxfendazole metabolic processes and provided insight into the significance of presystemic metabolism in oxfendazole and metabolite disposition. Oxfendazole clinical pharmacokinetics was best described by a one-compartment model with nonlinear absorption and linear elimination. Oxfendazole apparent clearance and apparent volume of distribution were estimated to be 2.57 liters/h and 35.2 liters, respectively, at the lowest dose (0.5 mg/kg), indicating that oxfendazole is a low extraction drug with moderate distribution. The disposition of both metabolites was adequately characterized by a one-compartment model with formation rate-limited elimination. Fenbendazole formation from oxfendazole was primarily through systemic metabolism, while both presystemic and systemic metabolism were critical to the formation of oxfendazole sulfone. Our model adequately captured the concentration-time profiles of both oxfendazole and its two metabolites in healthy adults over a wide dose range. The model can be used to predict oxfendazole disposition under new dosing regimens to support dose optimization in humans.

PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT.

Clazosentan's potential QT liability was investigated in a thorough QT study in which clazosentan was administered intravenously as a continuous infusion of 20 mg/h immediately followed by 60 mg/h. Clazosentan prolonged the placebo-corrected change-from-baseline QT interval corrected for RR with Fridericia's formula (ΔΔQTcF) with the maximum QT effect occurring 4 h after the maximum drug concentration, apparently associated with vomiting. The delayed effect precluded the standard linear modeling approach. This analysis aimed at characterizing the concentration-QT relationship in consideration of RR-QT hysteresis, concentration-ΔΔQTcF hysteresis, and the influence of vomiting. Nonlinear mixed-effects modeling was applied to characterize pharmacokinetics and pharmacodynamics, i.e., ΔΔQTcF. Simulations were used to predict ΔΔQTcF for expected therapeutic dose used in Phase 3 clinical development. Correction for RR-QT hysteresis did not influence ΔΔQTcF to a relevant extent. Pharmacokinetics of clazosentan were best described by a linear two-compartment model. The delayed QT prolongation was characterized by an indirect-response model with loglinear drug effect. Vomiting had no statistically significant influence on QT prolongation despite apparent differences between subjects vomiting and not vomiting, probably since vomiting occurred mostly after the main QT prolongation. Following a simulated 3-h infusion of 15 mg/h of clazosentan, the upper bound of the predicted 90% CI for mean ΔΔQTcF was expected to exceed the 10-ms regulatory threshold of concern with maximum effect 3.5 h after end of infusion. TRN: NCT03657446, 05 Sep 2018.

A Population Pharmacokinetic Analysis of Continuous Infusion of Cloxacillin during Staphylococcus aureus Bone and Joint Infections.

Intravenous administration of antibiotics is recommended during the early phase of methicillin-susceptible S. aureus (MSSA) bone and joint infection (BJI). We sought to compare the plasma concentrations of cloxacillin administered alternately by continuous and intermittent infusion (CI and ItI) in patients with MSSA BJI. In this prospective crossover trial, patients were randomly assigned to receive either 3 days of CI (two 75-mg/kg 12-h cloxacillin infusions per day) and then 3 days of ItI (four 37.5-mg/kg 1-h cloxacillin infusions per day) or vice versa. The drug concentration measurement was performed on day 3 of each type of administration at 1, 6, and 11 h and at 1, 2, 3, 4, and 6 h after the beginning of CI and ItI, respectively. We used the nonparametric algorithm NPAG to estimate population pharmacokinetic (PK) parameters. The final model was used to perform pharmacokinetic/pharmacodynamic (PK/PD) simulations and calculate the probabilities of target attainment (PTA) for several ItI and CI dosing regimens. We considered two PK/PD targets of time spent above the MIC for free cloxacillin concentrations (fT>MIC): 50 and 100%. Eighty-four concentrations from 11 patients were analyzed. A two-compartment model adequately described the data. ItI with q6h regimens and short 1-h infusions of 2,000 or 3,000 mg were associated with low PTA, even for the low target (50% fT>MIC) while 3-h infusions and continuous infusions (6 to 12 g/day) were associated with a PTA of >90% for an MIC up to 0.5 mg/liter. These results support the use of prolonged or continuous infusion of cloxacillin in patients with BJI.

Novel Approach for the Bioequivalence Assessment of Topical Cream Formulations: Model-Based Analysis of Tape Stripping Data Correctly Concludes BE and BIE.

PURPOSE: The purpose of this study was (a) to suggest a novel dermatopharmacokinetic (DPK) approach from which pharmacokinetic parameters relevant to the bioequivalence (BE) assessment of a topical formulation can be deduced while circumventing the need for numerous measurements and assumptions, and (b) to investigate whether this approach enables the correct conclusion of BE and bioinequivalence (BIE). METHODS: Bioequivalent and bioinequivalent formulations of acyclovir were compared versus a reference product (Zovirax®). Tape Stripping was conducted at only one dose duration during the uptake phase to generate drug content in stratum corneum versus time profiles, each time point corresponding to one stripped layer. Nonlinear mixed effect modeling (ADAPT5®) (MLEM algorithm) was used to fit the DPK data and to estimate the rate (Kin) and extent (FS) of drug absorption/input into the skin. Results were evaluated using the average BE approach. RESULTS: Estimated exposure metrics were within the usual BE limits for the bioequivalent formulation (FS: 102.4 [90%CI: 97.5-107.7]; Kin: 94.2 [90%CI: 83.7-106.0]), but outside those limits for the bioinequivalent formulation (FS: 43.4 [90%CI: 27.9-67.6]; Kin: 54.5 [90%CI: 36.6-81.1]). CONCLUSIONS: The proposed novel DPK approach was shown to be successful, robust and applicable to assess BE and BIE correctly between topical formulations.

A clinical population pharmacokinetic/pharmacodynamic model for BIIB059, a monoclonal antibody for the treatment of systemic and cutaneous lupus erythematosus.

A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model. The data included single and multiple dosing of intravenous and subcutaneous BIIB059. BDCA2 internalization (PD marker) was measured for all subjects by monitoring reduction of BDCA2 on pDC cell surface and used for development of the popPD model. A two-compartment popPK model with linear plus non-linear elimination was found to best describe BIIB059 PK. BDCA2 levels were best captured using an indirect response model with stimulation of the elimination of BDCA2. Clearance in SLE subjects was 25% higher compared to HV (6.87 vs 5.52 mL/h). Bodyweight was identified as only other covariate on clearance and central volume. The estimates of EC50 and Emax were 0.35 µg/mL and 8.92, respectively. No difference in EC50 and Emax was observed between SLE and HV. The popPK/PD model described the data accurately, as evaluated by pcVPCs and bootstrap. The presented popPK/PD model for BIIB059 provides valuable insight into the dynamics and dose-response relationship of BIIB059 for the treatment of SLE and CLE and was used to guide dose selection for the Phase 2 clinical study (NCT02847598).

Model-based evaluation of low-dose factor VIII prophylaxis in haemophilia A.

INTRODUCTION: The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study. AIM: To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing. METHODS: For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1 IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting. RESULTS: A treatment regimen of 10 IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration. CONCLUSION: Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models.

Estimation of Phenytoin Pharmacokinetic Parameters in Saudi Epileptic Patients.

OBJECTIVE: This study aimed to assess the population pharmacokinetics of phenytoin in Saudi patients and identify factors affecting therapeutic parameters. METHOD: A retrospective chart review was performed at King Saud University Medical City on patients treated with oral phenytoin. We used Monolix 4.4. for population pharmacokinetic modeling. A base model was developed to investigate several covariates, including age, gender, weight, total daily dose (TTD), and liver function test results. RESULTS: The analysis included a total of 81 phenytoin plasma concentrations from 43 patients (70% male). Patients' mean (± SD) age was 41 (±18.7) years and body weight was 65.4 (±17.7) kg. The patients received a phenytoin TDD of 330.5 (±104.5) mg/day, resulting in a trough concentration of 11.2 (±10.3) mg/L. The data were sufficiently described by the one-compartment open model with linear absorption and nonlinear elimination processes. Average parameter estimates for phenytoin volume of distribution (V), maximal elimination rate (Vmax), and Michaelis-Menten constant (Km) were 0.61 L/h/kg, 6.12 mg/kg/day, and 5.33 mg/L, respectively. The most significant covariates on phenytoin Vmax and Km were the age and body weight of the patients, along with valproic acid (VPA) cotherapy. CONCLUSION: The population pharmacokinetic model of phenytoin in Saudi patients found significant interindividual variability between subjects, which was affected by the patients' age, body weight, and VPA cotherapy as the most significant covariates on phenytoin Vmax and Km. To provide guidance in drug dosage decisions, further studies are required to evaluate all factors that may potentially influence the pharmacokinetics of phenytoin.

Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch.

Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis revealed ideal body weight was not a significant covariate on the PK of danvatirsen; nor was age, sex or race. The model-based simulation suggested that steady state weekly AUC and Cmax were very similar between 3 mg/kg and 200 mg flat dosing (geometric mean of AUC: 62.5 vs. 63.4 mg h/L and Cmax: 26.2 vs. 26.5 mg/L for two dose groups) with slightly less overall between-subject variability in the flat dosing regimen. The switch to flat dosing was approved by multiple regulatory agencies, including FDA, EMA, PMDA and ANSM. Several ongoing studies have been evaluating flat dosing. Interim analysis from an ongoing study (D5660C00016, NCT03421353) has shown the observed steady state concentration from 200 mg flat dose is in agreement with the model predictions. The population PK model could be further utilized in subsequent exposure-response efficacy and safety modelling.

Routine clinical care data for population pharmacokinetic modeling: the case for Fanhdi/Alphanate in hemophilia A patients.

Fanhdi/Alphanate is a plasma derived factor VIII concentrate used for treating hemophilia A, for which there has not been any dedicated model describing its pharmacokinetics (PK). A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project. WAPPS-Hemo provided individual PK profiles for hemophilia patients using sparse observations as provided in routine clinical care by hemophilia centers. Plasma factor activity measurements and covariate data from hemophilia A patients on Fanhdi/Alphanate were extracted from the WAPPS-Hemo database. A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check (pcVPC), cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data. Plasma factor activity measurements from 92 patients from 12 centers were used to derive the model. The PK was best described by a 2-compartment model including between subject variability on clearance and central volume, fat free mass as a covariate on clearance, central and peripheral volumes, and age as covariate on clearance. Evaluations showed that the developed population PK model could predict the PK parameters of new individuals based on limited sampling analysis and cross and external evaluations with acceptable precision and bias. This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data.

Population Pharmacokinetics of Intravenous Polymyxin B from Clinical Samples.

A retrospective study was conducted in hospitalized patients receiving intravenous polymyxin B who underwent therapeutic drug monitoring during treatment. The aim of this study was to assess the population pharmacokinetics (PK) of intravenous polymyxin B in patients with variable total body weights and create a population model for clinical use. Nonlinear mixed-effects modeling analyses were performed. A total of 43 patients were included, and 70% of these patients were male. The median age was 58 years, and the median weight was 78 kg. The median polymyxin B dose was 180 mg/day or 2.8 mg/kg/day. A one-compartment model described the polymyxin B PK well with conditional mean parameter estimates of a clearance (CL) of 2.37 liters/h and a volume of distribution of 34.4 liters and can be employed for clinical population modeling. Total body weight was not significantly associated with CL (Akaike information criterion, 361.6 for the weight-based model versus 359.5 for the non-weight-based model). These data suggest that dosing according to patient body weight requires further exploration. Greater study is needed to assess the relationships between polymyxin B exposures and efficacy and toxicity.

Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis.

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass.

The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CLCR). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval (fTMIC) of 65% for an MIC of 8 mg/liter in patients with a CLCR of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CLCR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CLCR values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CLCR values (≤30 ml/min).

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

AIMS: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability. RESULTS: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell. CONCLUSIONS: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory Emax function of Cmin on the seizure mean, where Emax exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.