Population Pharmacokinetic Methods Research Articles

Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients

ObjectiveUsage of tacrolimus is complicated by its narrow therapeutic index and wide between- and within-subject pharmacokinetic variability. We aimed to obtain more information regarding the influence of various covariates on...

Vancomycin in Pediatric Patients with Solid or Hematological Malignant Disease: Predictive Performance of a Population Pharmacokinetic Model and New Optimized Dosing Regimens.

The application of population pharmacokinetic models and Bayesian methods offers the potential to develop individualized therapeutic approaches. The current study presents an external evaluation of a vancomycin pharmacokinetic model in a pediatric cancer population and proposes an easy-to-use chart for clinicians for a priori vancomycin schedule adaptation to achieve target concentration. External evaluation of a population pharmacokinetic model of vancomycin administered via continuous infusion was realized in a new retrospective dataset of pediatric patients with cancer. The published population pharmacokinetic model was implemented in NONMEM 7.3 with the structural and variance parameter values set equal to estimates previously reported. Predictive performance was assessed by quantifying bias and accuracy of model prediction. Normalized prediction distribution errors were also evaluated. Dosage simulations were performed according to the target concentration. A total of 77 patients were included in this study, representing 146 vancomycin courses and 289 concentrations. The model adequately predicted vancomycin concentrations (median prediction error % of - 9.4%, median |PE|% of 24.1%). Based on simulation results, vancomycin dosage (mg/kg) should be adapted for each child on the basis of body weight and cyclosporine coadministration. The model previously proposed by Guilhaumou et al. in pediatric patients with solid or hematological malignant disease was externally validated. Simulations have enabled the description of new dosage schedules and creation of a chart to help clinicians adapt vancomycin dosage.

A Phase I/II Study of GMI-1271, a Novel E-Selectin Antagonist, in Combination with Induction Chemotherapy in Relapsed/Refractory and Elderly Previously Untreated Acute Myeloid Leukemia; Results to Date

BackgroundThe treatment of patients with relapsed acute myeloid leukemia (AML) remains a significant challenge with poor outcomes due to a low response rate. Although cytotoxic chemotherapy remains the standard approach for treatment, novel agents are needed to improve clinical outcomes. Binding of leukemic blasts to E-selectin (E-sel), an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-sel, putatively disrupting leukemia cell survival pathways and enhancing chemotherapy response. We performed a phase 1/2 trial of GMI-1271 plus MEC (mitoxantrone, etoposide and cytarabine) for the treatment of relapsed/refractory (R/R) and a pilot study adding GMI-1271 to 7+3 for previously untreated elderly patients with AML.MethodsA phase 1/2 open label trial of patients with R/R AML, with escalation of a single cycle of GMI-1271 across 3 dose levels combined with MEC, was conducted to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antileukemic activity. In addition, a pilot study was performed at the recommended phase 2 dose (RP2D) plus infusional cytarabine and idarubicin (7+3) in patients ≥60 years with untreated AML. Eligible patients (R/R AML) had an ECOG score of 0-2, received ≤2 prior induction regimens, WBC <20K (raised to <40K after 2 dose levels), no active CNS disease, and adequate renal and hepatic function. Eligibility for elderly patients in the untreated AML group was similar. GMI-1271 was administered with chemotherapy (24 hours prior, throughout, and 48 hours post induction). Dose limiting toxicity (DLT) was defined as myelosuppression beyond day 42 in the absence of disease or Grade 3 non-hematologic toxicity attributable to GMI-1271 and not resolving to Grade 2 by day 42. PK data were analyzed by population PK methods. PD for on-target activity was assessed by change from baseline in plasma sE-selectin levels (sE-sel) compared by 2-way analysis of variance.ResultsThe phase 1 (Ph1) dose escalation in the R/R AML arm was completed with 19 subjects treated with GMI-1271 BID at 5 mg/kg (N=6), 10 mg/kg (N=7), and 20 mg/kg (N=6). The median age was 51 (range 26-77); 13 were male; 6 were refractory to prior intensive induction; 10 relapsed in ≤12 mos and 3 in >12 mos; number of prior induction regimens: 1 (N=15) and 2 (N=4); risk based on the SWOG cytogenetic classification was intermediate (9) or unfavorable (10). There were no DLTs observed in the R/R dose escalation and no early deaths (30 d). Transient mucositis developed in only 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (5 mg/kg). Median time to count recovery was 37d (ANC >1K) and 35 d (platelets >100K) in responders. AEs were typical for MEC.Ph1 CR/CRi rate was 47% (42% CR%) with no observable dose response; 26% proceeded to subsequent stem cell transplant. Six of 9 remain in CR at data cut-off. Median OS and PFS have not been reached. One subject >70yrs with refractory disease who achieved CR (negative by flow) was retreated with GMI-1271/MEC again off protocol and remains in CR (9mo).PK analysis showed linear kinetics; an average 50 y.o. had clearance 1.28 L/h with elimination t1/2>3h; Cl decreased 2%/yr of increased age, and was 28% lower than in healthy adults. No accumulation was seen. Time over IC50 for E-sel binding was >50% of the dosing interval for most patients at 10 mg/kg, and well in excess of effective preclinical exposure. PD analysis showed sE-sel on Day 8 decreased below baseline (p<0.0013) with no dose response, suggesting on-target activity at all dose levels. Normal HSCs were not mobilized into the periphery after sentinel GMI-1271 dose. RP2D was determined to be 10 mg/kg BID based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and similar on-target PD and clinical outcomes.To date, 10 patients enrolled on the Ph2 R/R AML arm; an additional 37 will be enrolled. In the previously untreated elderly AML arm, 3 patients enrolled in the safety run-in and no DLTs were observed, therefore an additional 22 patients will be enrolled. Updated response data will be presented at ASH.ConclusionWe report on early clinical assessment of novel E-selectin antagonist GMI-1271 in R/R AML patients, with a high response rate (CR/CRi 47%) in this challenging group. No significant toxicities and no DLT were observed for GMI-1271. Ph2 dose expansion is ongoing. DisclosuresDeAngelo:Celgene: Consultancy; Ariad: Consultancy; Baxter: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Liesveld:Onconova: Other: Data safety monitoring board; Astex: Honoraria; glycomimetics: Research Funding. O'Dwyer:Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Becker:GlycoMimetics: Research Funding.

Invasiveness of pharmacokinetic studies in children: a systematic review

ObjectivesTo explore whether pharmacokinetic (PK) studies in paediatric patients are becoming less invasive. This will be evaluated by analysing the number of samples and volume of blood collected for each...

Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency.

POPULATION PHARMACOKINETICS OF ENROFLOXACIN AND ITS METABOLITE CIPROFLOXACIN IN THE GREEN SEA URCHIN (STRONGYLOCENTROTUS DROEBACHIENSIS) FOLLOWING INTRACOELOMIC AND IMMERSION ADMINISTRATION.

Sea urchin mass mortality events have been attributed to both infectious and noninfectious etiologies. Bacteria, including Vibrio spp. and Pseudoalteromonas spp., have been isolated during specific mortality events. Aquarium collection sea urchins are also subject to bacterial infections and could benefit from antimicrobial treatment, but pharmacokinetic studies have been lacking for this invertebrate group until recently. This study evaluated the pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin in the green sea urchin (Strongylocentrotus droebachiensis) after intracoelomic injection and medicated bath immersion administration. The utility of a population pharmacokinetic method using nonlinear mixed effects modeling (NLME) was also evaluated. Thirty sea urchins were assigned to either the injection or immersion group. Twelve study animals and three untreated controls were utilized for each administration method: enrofloxacin 10 mg/kg intracoelomic injection or a 6-hr enrofloxacin 10 mg/L immersion. Each animal was sampled four times from 0 to 120 hr. Water samples were collected during immersion treatment and posttreatment time points in both groups. Hemolymph and water sample drug concentrations were analyzed using high-performance liquid chromatography, and pharmacokinetic parameters were determined using an NLME population pharmacokinetic method. Enrofloxacin concentrations were fit to a two-compartment model with first-order input for the intracoelomic injection group. The enrofloxacin elimination half-life (t½), peak hemolymph concentration (CMAX), and area under the curve (AUC) were 38.82 hr, 90.92 μg/ml, and 1,199 hr·μg/ml, respectively. Enrofloxacin was modeled to a one-compartment model with first-order input for the immersion treatment. The enrofloxacin t½, CMAX, and AUC were 33.46 hr, 0.48 μg/ml, and 32.88 hr·μg/ml, respectively. Ciprofloxacin was detected in trace concentrations in all hemolymph samples, indicating minimal production of this metabolite. The concentrations of enrofloxacin achieved far exceeded minimum inhibitory concentrations reported for teleost pathogens. No adverse effects were associated with enrofloxacin administration by either treatment method or from hemolymph sampling.

Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature human infants, which may persist through adulthood. Airway inflammation has been firmly established in the pathogenesis of BPD. Previous studies to reduce airway inflammation with high-dose dexamethasone demonstrated adverse neurological outcomes, despite lower incidences of BPD. Instillation of budesonide and surfactant can facilitate early extubation and reduce the incidence of BPD and death among very low birth weight infants. However, the pharmacokinetics of budesonide and its distribution into the lung and brain are unknown. Therefore, 5 premature lambs were administered 0.25 mg/kg budesonide, with surfactant as the vehicle. Plasma and tissue samples were taken from the lambs for measurement of budesonide, 16α- hydroxy prednisolone, and budesonide palmitate using LC/MS/MS. Peak plasma budesonide concentrations were inversely correlated with the oxygenation index (correlation coefficient of -0.75). plasma budesonide concentrations were extremely low (~10% of expected) for two lambs that had high oxygenation indices and were excluded from further analyses. For the remaining 5 premature lambs, a non-compartmental analysis demonstrated an AUCinf of 148.77 ± 28.16 h*μg/L, half-life of 4.76 ± 1.79 h, and Cmax of 46.17 ± 17.71 µg/L. Using population pharmacokinetic methods, a onecompartment model with exponential residual error and first-order absorption adequately described the data. The apparent clearance and apparent volume of distribution of budesonide were estimated at 6.29 L/h (1.99 L/h/kg) and 29.1 L (9.2 L/kg), respectively. Budesonide and budesonide palmitate, but not 16α-hydroxy prednisolone, were detected in lung tissue. In this study, budesonide and its metabolites were not detected in the brain, which suggests that intratracheal instillation suggests that after local pulmonary deposition, there is no evidence of budesonide accumulation in the central nervous system. Overall, these results show that peak plasma budesonide concentrations are inversely correlated with the oxygenation index and that lung-specific delivery of budesonide avoids accumulation of budesonide in the brain.

Population Pharmacokinetics of Inhaled Fluticasone Furoate and Vilanterol in Subjects with Chronic Obstructive Pulmonary Disease

Background and ObjectivesPrevious pharmacokinetic studies of the inhaled corticosteroid, fluticasone furoate (FF), and the long-acting, beta2-receptor agonist, vilanterol (VI) have been performed in relatively small populations using non-compartmental pharmacokinetic methods and censored data (due to low drug exposure relative to assay sensitivity). This paper presents a population pharmacokinetic analysis, utilizing pooled concentration–time data from clinical studies in healthy subjects and from global trials in patients with chronic obstructive pulmonary disease (COPD). The objective of this analysis was to characterize the population pharmacokinetics of FF and VI following once-daily inhalation dosing of FF/VI or the individual components (FF and VI) and to identify significant covariates that impact systemic exposure to FF and VI in this population.MethodsPopulation pharmacokinetic methods that maximize the likelihood of all data were developed to describe systemic exposure to FF and VI following once-daily FF/VI, FF, or VI, and to identify significant covariates that impact the pharmacokinetics. COPD patients (N = 1225 for the FF analysis and N = 1091 for the VI analysis; 94 and 93 % of total data, respectively) and healthy subjects contributed to the analysis.ResultsFF data were described by a two-compartment model with first-order absorption and elimination. The population grouping “race” was a significant covariate on inhaled clearance (CL/F). The area under the curve over 24 h (AUC0–24) for FF was higher for East Asian, Japanese, and South East Asian (average 23–30 %) and Asian Central, White Arabic, American Indian/Native Alaskan, and ‘other’ (10–26 %) subjects compared with White/Caucasians. VI pharmacokinetics were described by a three-compartment model with zero-order absorption and first-order elimination. Significant demographic covariates identified to affect pharmacokinetics of VI were age [on CL/F and central volume (V 1/F)], bodyweight (on CL/F), sex and smoking (on V 1/F).ConclusionsWhile significant effects of the covariates were observed in this study, the magnitude of these effects on systemic exposure is not large enough to warrant FF/VI dosage adjustment in patients with COPD.Electronic supplementary materialThe online version of this article (doi:10.1007/s13318-015-0303-4) contains supplementary material, which is available to authorized users.

Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells.

The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.

The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD

Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods. The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5mg/day and sertraline at 25-50mg/day. Doses were increased to a maximum of 20mg/day for olanzapine and 200mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration. Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p<0.005) by 25-35% depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance. Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.

Predictive performance of Vancomycin population pharmacokinetic models in Iranian patients underwent hematopoietic stem cell transplantation

Objective:Many hematopoietic stem cell transplantation (HSCT) patients receive vancomycin empirically during febrile neutropenia. There are several models for estimation of vancomycin pharmacokinetic parameters and calculation of initial dosing regimen accordingly. However, the performance of these methods in HSCT patients remained to be evaluated. The aim of the study was to determine which of the vancomycin population pharmacokinetic methods best fit Iranian HSCT patients.Methods:In order to evaluate predicted performance of seven vancomycin population pharmacokinetic models, the pharmacokinetic parameters of patients were estimated using each model's equations. Then the predicted steady-state trough vancomycin concentration was calculated based on each model's parameters and using a formula based on Sawchuk–Zaske method. The predicted steady-state trough vancomycin concentration and the real measured concentrations were compared to see which method was the most precise and least biased using mean squared error (MSE) and mean prediction error (ME) respectively.Findings:Forty-six patients (65% men) were included in the study. Calculated metrics showed a range of 38% under-prediction bias with Rodvold to 34% over-prediction bias with Matzke and Burton models. Birt and revised Burton methods showed no significant bias (ME [95% confidence interval (CI)]: –0.067 [–0.235–0.101] and 0.066 [–0.105–0.238]). Birt and revised Burton were not different significantly considering MSE (95% CI) of 0.385 (0.227–0.544) and 0.401 (0.255–0.546), respectively. Comparisons of precision with naive predictors revealed a delta MSE (95% CI) of –0.128 (–1.379–1.890) for Birt and 0.026 (–0.596–0.940) for revised Burton models.Conclusion:Although the Birt and Burton revised methods performed well, none of the studied models showed acceptable performance to be implemented as a routine method for initial dose calculation in HSCT patients. A vancomycin pharmacokinetic model specific for this high-risk subpopulation of Iranian patients should be designed and validated.

Simulation studies on the estimation of total area under the curve in the presence of right-tailed censoring

The effect of extrapolated area (%AUCextrap) on estimating mean AUCinf in a simulated single-dose clinical trial was examined. Concentration-time (C-t) profiles from 12 to 36 subjects for 1- and 2-compartment models after single dose administration were simulated with increasing right-tailed censoring. Each subject's %AUCextrap and AUCinf was calculated using eight different methods, including noncompartmental analysis (NCA), population-based methods, and maximum likelihood (ML) accounting for censoring. Each method's geometric mean AUCinf and percent relative error (PRE) from the true AUCinf was calculated. This was repeated 100 times and the mean PRE (MPRE) was calculated. Mean %AUCextrap ranged from 1 to ~30 % for the 1-compartment and 2 to 32 % for the 2-compartment model at the lowest and highest degree of censoring, respectively. NCA methods using all subjects to estimate the population mean AUCinf had similar or less bias (within ± 20 %) than when those subjects with >20 % %AUCextrap were removed. Using Cpred compared to Clast in the calculation of individual AUCinf resulted in no performance improvement. Linear mixed effects models to estimate λz and ML methods accounting for censoring resulted in either no improvement or increased bias when censoring was high. Population pharmacokinetic method bias was dependent on the nature of the C-t profile. When the C-t profile declined biphasically, population models had higher bias than NCA methods but were superior when the C-t profile decline in a log-linear manner. It is recommended that subjects with high %AUCextrap should not be removed from the estimation of mean AUCinf in NCA analyses.

Pharmacokinetic Properties of Single-Dose Primaquine in Papua New Guinean Children: Feasibility of Abbreviated High-Dose Regimens for Radical Cure of Vivax Malaria

Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (Cmax) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher Cmax for PMQ and CPMQ, respectively. All predicted median Cmax concentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group.

Novel Population Pharmacokinetic Method Compared to the Standard Noncompartmental Approach to Assess Bioequivalence of Iron Gluconate Formulations

Iron-containing products are atypical in terms of their pharmacokinetic properties because iron is only removed by plasma sampling and is non-linear. This study aims to present a novel way of assessing the relative bioavailability of two sodium ferric gluconate complex (SFGC) formulations and compare this approach to a standard previously published noncompartmental approach. Data were from open-label, randomized, single-dose studies (Study 1 was parallel whereas Study 2 was crossover). Subjects with low but normal iron levels were infused IV SFGC in sucrose by GeneraMedix Inc. and/or Ferrlecit ® Injection (Watson Laboratories Inc.). In Study 1 (n=240), 125 mg was infused over 10 minutes. In Study 2 (n=29), 62.5 mg was infused over 30 minutes. Samples were assayed for total iron (TI) and transferrin-bound iron (TBI) over 36 hours (Study 1) or 72 hours (Study 2) post-dose. Studies 1 and 2 used standard noncompartmental analysis. Study 2 also used population PK (PPK) analyses with ADAPT 5®. The final model predicted SFGC area-under-the-curve (AUCpred) and maximal concentration (Cmaxpred). Analyses of variance was conducted on ln-transformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%. For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC0-36 were 100.4 (96.5 - 104.5) and 99.7 (94.2 - 105.5). For TBI, results for TI baseline-corrected Cmax and AUC0-36 were 86.8 (82.7 - 91.1) and 92.4 (85.6 - 99.7). For Study 2, a multi-compartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmaxpred and AUCpred were 89.9 (85.9 - 94.0) and 89.7 (85.7 - 93.9), while ratios and 90% CI obtained from the noncompartmental analysis of Study 2 did not meet BE criteria because of low power. Both the standard and PPK modeling approach suggested bioequivalence between the iron products. However, with the PPK method, less subjects were required to meet study objectives compared to the standard noncompartmental approach which required considerably more subjects (29 vs 240).

Two general methods for population pharmacokinetic modeling: non-parametric adaptive grid and non-parametric Bayesian

Population pharmacokinetic (PK) modeling methods can be statistically classified as either parametric or nonparametric (NP). Each classification can be divided into maximum likelihood (ML) or Bayesian (B) approaches. In this paper we discuss the nonparametric case using both maximum likelihood and Bayesian approaches. We present two nonparametric methods for estimating the unknown joint population distribution of model parameter values in a pharmacokinetic/pharmacodynamic (PK/PD) dataset. The first method is the NP Adaptive Grid (NPAG). The second is the NP Bayesian (NPB) algorithm with a stick-breaking process to construct a Dirichlet prior. Our objective is to compare the performance of these two methods using a simulated PK/PD dataset. Our results showed excellent performance of NPAG and NPB in a realistically simulated PK study. This simulation allowed us to have benchmarks in the form of the true population parameters to compare with the estimates produced by the two methods, while incorporating challenges like unbalanced sample times and sample numbers as well as the ability to include the covariate of patient weight. We conclude that both NPML and NPB can be used in realistic PK/PD population analysis problems. The advantages of one versus the other are discussed in the paper. NPAG and NPB are implemented in R and freely available for download within the Pmetrics package from www.lapk.org.

Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition)

Peter W. Collins, Elizabeth Chalmers, Daniel P. Hart, Ri Liesner, Savita Rangarajan, Kate Talks, Mike Williams and Charles R. Hay School of Medicine, Cardiff University, University Hospital of Wales, Wales, Royal Hospital for Sick Children, Glasgow, The London School of Medicine and Dentistry, Royal London Hospital, Barts, Queen Mary University, London, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Royal Victoria Infirmary, Newcastle upon Tyne, Birmingham Childrens’ Hospital NHS Foundation Trust, Birmingham and Central Manchester University Hospitals, Manchester, UK

Intravenous Oxycodone for Pain Relief in the First Stage of Labour – Maternal Pharmacokinetics and Neonatal Exposure

Physiological changes during pregnancy may change pharmacokinetics of compounds. Oxycodone is an increasingly used opioid agonist in acute pain management but its pharmacokinetics in labouring women has not been established. We studied the maternal pharmacokinetics and neonatal exposure of intravenous oxycodone for pain relief in the first stage of labour. The study was prospective, open-labelled and with a control group. After informed consent, 15 nulliparous parturients and newborns, and newborns in a control group were studied. In the study group, oxycodone boluses of 1mg i.v., up to a cumulative dose of 5mg, was administered when labour pain score was 5/10 or higher. As the control group, 30 other newborns after uncomplicated deliveries with no systemic opioids were assessed for the neonatal outcome. In the study group, maternal pharmacokinetics of oxycodone was measured from plasma concentrations during labour, and neonatal exposure was assessed from umbilical plasma samples using population pharmacokinetic methods. Maternal plasma oxycodone concentration decreased with a median half-life of 2.6hr (range, 1.8-2.8). Oxycodone concentrations in the umbilical plasma 2.7μg/l (0.3-14.5) were similar as in maternal plasma 2.4 (0.1-14.8)μg/l at the time of birth. No severe or unexpected adverse effects were noted. To conclude, firstly, maternal elimination half-life of i.v. oxycodone was significantly shorter than that reported in non-pregnant women, and secondly, maternal plasma oxycodone at the birth correlated well with neonatal umbilical concentrations and may, thus, be used as an estimate of neonatal exposure.

Predicting Plasma Concentration of Risperidone Associated With Dosage Change

Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change. Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study. The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (-1.3 to 1.4) for RIS and 1.0 (-1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively). Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients. Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults. A significant difference in erlotinib clearance (P = 0.0001), when expressed in L·h(-1)·kg(-1), was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L·h(-1)·kg(-1), SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC. The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic-pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m(2)/day) compared with adults (90 mg/m(2)/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities.

Integrated Population Pharmacokinetics of Etanercept in Healthy Subjects and in Patients With Rheumatoid Arthritis Ankylosing Spondylitis

Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first-order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2-compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics.