Average Steady-state Concentration Research Articles

Abstract 4634: Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies

Abstract Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are B-cell malignancies with initial high response rate to chemoimmunotherapy, but are largely considered incurable. Ibrutinib (PCI-32765), an oral Bruton's tyrosine kinase inhibitor recently approved to treat MCL, is under development for other B-cell malignancies. We developed a population pharmacokinetic (PK) model for describing data collected to date in clinical trials with ibrutinib. Ibrutinib plasma data were available from 3 clinical trials: 1) a phase 1 dose-escalation study in recurrent B-cell malignancies (doses: 1.25-12.5 mg/kg and 560 mg fixed); 2) a phase 1b/2 dose-finding study in CLL (doses: 420 and 840 mg); 3) an open-label, phase 2, fixed-dose study in MCL (dose: 560 mg). Overall, ≈3477 observations were collected in 245 patients following single and repeated daily dosing on different treatment days. A 2-compartment model with sequential zero to first order absorption and first order elimination was implemented. Analyses were performed with a log-transform-both-sides approach. Additive and exponential models were used to describe residual and inter-individual variability, respectively. The first-order conditional estimation method was implemented using NONMEM v 7.1. A linear model constructed with data collected following single and repeated doses of ibrutinib at different dose levels demonstrated that the PK was dose and time independent. Ibrutinib was rapidly absorbed and was characterized by a high oral plasma clearance (≈1000 L/h with between-subject variability of 21.9%; this, for a dose of 560 mg, would lead to an average steady state concentration of ≈22 ng/mL, ie, ≈50 nM) and a high apparent volume of distribution at steady state (≈10,000 L). Though both values are confounded by absolute bioavailability, these values suggest that ibrutinib clearance and volume are high. The half-lives of distribution and terminal phases were estimated to be <1 h and ≈14 h, respectively. Administration of ibrutinib in fasting state was characterized by a 67% relative bioavailability compared to both meal conditions used in the clinical trials and administration after a high-fat meal. The PK parameters were not found to be significantly different between studies and clinical indications. Body weight and coadministration of antacids had a marginal effect on volume of distribution and duration of absorption processes, respectively. No significant effect of covariates such as age, gender, patient pretreatment, or clinical chemistry data was found. Population parameters and inter-individual variability were estimated with good precision. The model provided satisfactory goodness of fit, individual fittings, and visual predictive checks. In conclusion, the proposed population PK model was able to accommodate the plasma concentration-time profiles of ibrutinib across various trials. Citation Format: Eleonora Marostica, Juthamas Sukbuntherng, David Loury, Jan De Jong, Xavier Woot de Trixhie, An Vermeulen, Giuseppe de Nicolao, Susan O'Brien, John C. Byrd, Ranjana Advani, Jesse McGreivy, Italo Poggesi. Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4634. doi:10.1158/1538-7445.AM2014-4634

Pharmacokinetics of orally administered duloxetine in children and adolescents with major depressive disorder.

Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program for duloxetine in the pediatric MDD population, which consisted of three clinical studies, provided extensive data on the safety, tolerability, and pharmacokinetics of duloxetine across a wide dose range in pediatric patients of differing ages, sex, body weights, and sexual maturation. The objectives were to characterize the pharmacokinetics of duloxetine based on population modeling following daily oral administration in children and adolescents aged 7-17 years diagnosed with MDD; to estimate the magnitude of between- and within-patient variability; to identify potential patient factors affecting duloxetine pharmacokinetics, and to compare duloxetine pharmacokinetics in the pediatric population with those characterized in adults. The analyses meta-dataset was created from pharmacokinetic and demographic data available from one phase II (open-label) and two phase III (randomized, double-blind) clinical trials of duloxetine in children and adolescents. Patients received 20-120 mg of oral duloxetine once daily. Duloxetine concentrations (a total of 1,581 concentrations) were obtained from 428 patients: 34% were children (aged 7-11 years) and 66% were adolescents (aged 12-18 years). Population modeling analyses were performed using nonlinear mixed-effects modeling and the first-order conditional estimation method with interaction. Patient factors were assessed for their potential influence on duloxetine apparent clearance (CL/F) and apparent volume of distribution (V d/F). Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the pediatric population were compared with those in adults. Duloxetine pharmacokinetics in pediatric patients was described by a one-compartmental model. Typical values of CL/F, V d/F, and half-life (t 1/2) at 60 mg/day of duloxetine were 79.7 L/h, 1,200 L, and 10.4 h, respectively. The between-patient variability in CL/F and V d/F was 68 and 87%, respectively, while within-patient variability was 57% (proportional error) and 2.04 ng/mL (additive error). Body surface area (BSA), dose, and race had a statistically significant effect on duloxetine pharmacokinetics. With a 2.2-fold increase in BSA, the CL/F increased about twofold. A sixfold increase in dose (20 to 120 mg) decreased CL/F by 32%. In American Indian patients, V d/F was 131% higher than the other races combined. Age, sex, body mass index, serum creatinine, cytochrome P450 2D6 predicted phenotype, and menarche status did not have a statistically significant effect. Estimates of CL/F and V d/F were higher in the pediatric population than in adults; subsequently, the average steady-state duloxetine concentration was approximately 30% lower in the pediatric population than in adults. Duloxetine pharmacokinetics was similar in children and adolescents with MDD. The statistically significant effects of dose, BSA, and race on duloxetine pharmacokinetics in pediatric patients did not appear to be clinically meaningful. At a given dose, the typical steady-state duloxetine concentrations in the pediatric population were lower than in adults, and the distribution of steady-state duloxetine concentrations in pediatric patients were typically in the lower range of concentrations in adults.

Randomised Pharmacokinetic Trial of Rifabutin with Lopinavir/Ritonavir-Antiretroviral Therapy in Patients with HIV-Associated Tuberculosis in Vietnam

BackgroundRifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured.MethodsThis was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir.ResultsSixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 – 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations.ConclusionsBased on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.Trial RegistrationClinicalTrials.gov NCT00651066

Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer

To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity of the PI3K/mTOR inhibitor PF-04691502, administered orally once daily. Escalating doses of PF-04691502 were administered to 23 patients with advanced solid tumors in sequential cohorts across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg. 14 additional patients were enrolled in an expansion cohort at the MTD to ensure at least five matched pre- and post-treatment biopsies for biomarkers of PI3K activity. The MTD of PF-04691502 was 8 mg orally once daily. There were three dose-limiting toxicities: one grade 3 fatigue at 8 mg, one grade 3 rash at 11 mg, and one intolerable grade 2 fatigue at 11 mg. Among 37 patients enrolled, treatment-related adverse events included fatigue, decreased appetite, nausea, hyperglycemia, rash, and vomiting. Across all dose levels, average steady-state plasma PF-04691502 concentrations approximated or exceeded the target concentration of 16.2 ng/mL required for ≥75 % tumor growth inhibition in preclinical models. PF-04691502 resulted in increased mean fasting serum glucose, insulin, and c-peptide levels, and produced partial blockade of PI3K signalling in five paired tumor biopsies, as demonstrated by reductions in phosphorylated Akt, FKHR/FKHRL1, and STAT3. No objective anti-tumor responses were observed. Daily oral administration of PF-04691502 was tolerable at 8 mg orally once daily, with a safety profile similar to other PI3K/mTOR inhibitors. PF-04691502 demonstrated PI3K pathway inhibition by changing glucose homeostasis, and by decreasing phosphorylation of downstream molecules in tumor tissue.

Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 1. Microdialysis Assessment of Brain Extracellular Fluid Concentrations in Patients with Acute Brain Injury

The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0-τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml(-1). This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.

Comprehensive Analysis Of The In Vitro Potency Of Ponatinib, and All Other Approved BCR-ABL Tyrosine Kinase Inhibitors (TKIs), Against a Panel Of Single and Compound BCR-ABL Mutants

BackgroundSecondary mutations in BCR-ABL are the most common cause of resistance to TKIs in patients (pts) with chronic myeloid leukemia (CML). Ponatinib is a potent pan-BCR-ABL TKI that has been shown to suppress the emergence of any single mutation in vitro, including T315I, at clinically achievable concentrations (40 nM), though higher concentrations were required to suppress emergence of certain compound mutations (2 mutations in the same BCR-ABL allele). Ponatinib has demonstrated significant clinical activity in pts in the phase 2 PACE trial, 60% of whom received 3 or more prior TKIs. Responses were observed for each of the 15 mutations present in >1 chronic phase CML pt at baseline, and no single mutation conferring resistance to ponatinib has emerged to date, though in some cases development of compound mutations has been observed. To gain a more precise understanding of the effects of specific mutations on the clinical efficacy of ponatinib, IC50s for ponatinib, and all other approved TKIs, against 31 single or compound BCR-ABL mutants were determined. To explore the relationship between in vitro potency and clinical efficacy, IC50s were related to “effective” TKI levels achieved in patients. MethodsTKI potency was assessed in engineered Ba/F3 cells by measuring cell viability at 72 hours. The effective plasma concentration for each TKI was calculated from published average steady-state concentration values for the recommended dose, and adjusted for the functional effects of protein binding. These effects were assessed by determining the degree to which TKI potency was reduced by the presence of physiological concentrations of human serum albumin (HSA) and alpha 1-acid glycoprotein (AAG). ResultsThe activity of ponatinib, and 5 other TKIs, against 21 single BCR-ABL mutants is shown in Figure A. Ponatinib potently inhibited viability of native BCR-ABL and all mutants, including T315I (IC50s (nM): 3-16). The IC50s for the other TKIs, excluding T315I (>4000 for all) ranged from: 201-10,000 (imatinib), 12-784 (nilotinib), 2-104 (dasatinib), 40-1,280 (bosutinib) and 18-5,216 (radotinib). IC50 values were compared to the effective plasma concentration for each TKI (Figure A). Mutants that have previously been associated with clinical resistance to a particular TKI tended to have IC50s that approached or substantially exceeded the effective concentration for that TKI, including most mutants for imatinib, E255K/V, Y253H, L248R, T315I for nilotinib, and V299L, F317C/I/V, T315A/I for dasatinib. The most problematic mutants for bosutinib predicted by this analysis were F317V, L248R, V299L, and T315I. Notably, all mutant IC50s fell below the effective concentration for ponatinib. The activity of all TKIs against 10 clinically-observed BCR-ABL compound mutants was also assessed. Four compound mutants had IC50s near or above the effective concentration for ponatinib (T315I+M351T, E255V+F317I, T315I+E255K, T315I+E255V) (Figure B). All 4, plus others, are also predicted to be problematic for the other TKIs. [Display omitted] ConclusionsRelating in vitro TKI potency to “effective” steady-state plasma concentrations in patients identified mutations known to confer clinical resistance to imatinib, nilotinib and dasatinib. This method of analysis suggests that ponatinib may be able to inhibit all single BCR-ABL mutants, but not all compound mutants, a prediction that is thus far consistent with results observed in patients. Compound mutations that are predicted to confer resistance to ponatinib are also predicted to confer resistance to all other approved TKIs. Early introduction of ponatinib may prevent the emergence of single mutations, and thus the sequential development of compound mutations. Disclosures:Gozgit:ARIAD: Employment, Equity Ownership. Schrock:ARIAD: Employment, Equity Ownership. Chen:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment.

Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in End-Stage Renal Disease Patients Receiving Continuous Ambulatory Peritoneal Dialysis

Colistin, administered intravenously as its inactive prodrug colistin methanesulfonate (CMS), is increasingly used as last-line therapy to combat multidrug-resistant Gram-negative bacteria. CMS dosing needs to be adjusted for renal function. The impact of continuous ambulatory peritoneal dialysis (CAPD) on the pharmacokinetics of both CMS and colistin has not been studied. No CMS dosing recommendations are available for patients receiving CAPD. Eight CAPD patients received a single intravenous CMS dose (150 mg colistin base activity [CBA]) over 30 min. Serial blood and dialysate samples, and cumulative urine where applicable, were collected over 25 h. CMS and colistin concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations were conducted. The total body clearance of CMS (excluding CAPD clearance) was 1.77 liters/h (44%) [population mean (between-subject variability)], while CAPD clearance was 0.088 liter/h (64%). The population mean terminal half-life of CMS was 8.4 h. For colistin, the total clearance/fraction of CMS metabolized to colistin (fm) (excluding CAPD clearance) was 2.74 liters/h (50%), the CAPD clearance was 0.101 liter/h (34%), and the mean terminal half-life was 13.2 h. Monte Carlo simulations suggested a loading dose of 300 mg CBA on day 1 and a maintenance dose of either 150 mg or 200 mg CBA daily to achieve a target average steady-state plasma colistin concentration of 2.5 mg/liter. Clearance by CAPD was low for both CMS and formed colistin. Therefore, CMS doses should not be increased during CAPD. Modeling and simulation enabled us to propose the first evidence-based CMS dosage regimen for CAPD patients.

Concentration–effect relationships with perampanel in patients with pharmacoresistant partial‐onset seizures

Although there is a general paucity of published pharmacokinetic (PK) data for new antiepileptic drugs (AEDs), PK analyses of pooled data from clinical studies of perampanel have recently been presented. We present PK/pharmacodynamic (PD) analyses of pooled data from phase III studies of perampanel describing efficacy and safety as a function of exposure, in order to determine whether a predictable concentration-effect relationship exists for perampanel efficacy and/or adverse events (AEs). The effects of concomitant enzyme-inducing AEDs (EIAEDs) and non-enzyme-inducing AEDs on the exposure, efficacy, and safety of perampanel are also considered. Three multicenter, randomized, double-blind, placebo-controlled phase III studies investigated the efficacy and safety of perampanel 2-12 mg in patients with uncontrolled partial-onset seizures despite prior therapy with two or more AEDs. From baseline onward, patients also received ongoing treatment with stable doses of one to three approved concomitant AEDs. AEs were monitored throughout the studies. Changes from baseline in seizure frequency and 50% responder rates were evaluated. Exposure to perampanel was predicted based on the actual (last) dose using a previously established PK model. A population PK/PD model for the relationship between perampanel exposure and seizure frequency was estimated using nonlinear mixed-effect modeling with first-order conditional estimation, whereas logistic analyses for responder rate and AEs were performed using SAS analysis software. The PK/PD population included 1,109 patients. Seizure frequency decreased linearly as predicted perampanel average steady-state plasma concentrations increased. Concomitant EIAEDs (carbamazepine, oxcarbazepine, and phenytoin) reduced exposure to perampanel but had no effect on the slope of the PD model-predicted relationship between exposure and reduction in seizure frequency. The probability of patients achieving a response was predicted to increase as perampanel average plasma concentration at steady state increased. No demographic, AED, region, or study covariate had any effect on the probability of achieving a positive treatment response to perampanel or on the slope of the exposure-response curve. Across the phase III studies, there were reports of dizziness (32.9%), somnolence (21.7%), fatigue (13.9%), irritability (12.3%), gait disturbance (9.1%), weight increase (6.1%), dysarthria (4.5%), and euphoric mood (0.5%); the model-predicted probability of these AEs increased significantly at higher exposure to perampanel (all p < 0.001). There was no effect of demographic variables or region on the probability of experiencing any of the AEs analyzed. PK and PD analyses have played a pivotal role in the clinical development of perampanel as an adjunctive treatment for pharmacoresistant partial-onset seizures. Phase III data suggest that a significant relationship exists between increases in perampanel plasma concentration (i.e., systemic exposure) and reductions in seizure frequency. In addition, increases in perampanel plasma concentration may potentially be associated with increases in AE rates. The model-predicted concentration-safety profile of perampanel does not appear to be affected by patient age, gender, or ethnicity. Although concomitant EIAEDs may influence perampanel PK, they do not appear to alter the relationship between perampanel plasma concentration and seizure frequency. Understanding these relationships between perampanel plasma concentration and clinical response will be valuable in utilizing this novel AED.

Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.

PurposeDasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit–risk profile of dasatinib 100 mg once daily, exposure–response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).Patients and methodsDasatinib exposure in patients with chronic myeloid leukemia in chronic phase was determined by population pharmacokinetic analysis of data from seven dasatinib clinical studies (N = 981), including the Phase III dose-optimization study (n = 567). Data from the Phase III study were then used to characterize exposure–response relationships for the four dasatinib treatment regimens investigated (100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily).ResultsMajor cytogenetic response was significantly (P < 0.01) associated with weighted average steady-state dasatinib plasma concentrations, and pleural effusion was significantly associated with trough concentration. Major cytogenetic response was also significantly associated with maintenance of uninterrupted dosing. The 100 mg once daily arm had the lowest steady-state trough concentration of the four dose arms investigated in the Phase III study, and although this arm also had the lowest weighted average steady-state dasatinib plasma concentration, it had the highest dose maintenance.ConclusionDasatinib dose optimization to 100 mg once daily from 70 mg twice daily significantly minimizes adverse events while maintaining efficacy by exploiting differences in the measures of exposure associated with efficacy and safety.

A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma.

2018 Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV's induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.

The ABCD of clinical pharmacokinetics.

The ABCD of clinical pharmacokinetics.

Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068, an Oral HIV-1 Attachment Inhibitor in HIV-1-Infected Subjects

BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells. Fifty HIV-1-infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068. The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log(10) copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding-adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated. Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted. Clinical Trials Registration.NCT01009814.

Pharmacokinetics and bioequivalence in the pig of two ivermectin feed formulations

Two premix products containing the endectocide ivermectin were compared for pharmacokinetic profiles and bioequivalence in young pigs. Test and reference articles were administered to individual pigs in-feed at 12-h intervals for a total of 14 doses. Plasma concentration-time profiles were compared after provision of the final doses of medicated feed, by which time steady-state concentrations of ivermectin had been achieved. The pharmacokinetic variables monitored were peak concentration (Cmax ), area under the curve (AUC)0-last , elimination half-life of the terminal phase (T1/2 λz) and average steady-state concentration (Css ), determined by noncompartmental analysis. Logarithmic transformation of the variables was carried out when appropriate. Analysis of data by the Classic Method yielded confidence intervals of 80.59-114.47 (for AUC0-last ), 90.38-119.68 (for Cmax ) and 84.70-111.96 (for Css ). It was concluded that the two articles were bioequivalent for ivermectin.

Impact of age, weight and concomitant treatment on lamotrigine pharmacokinetics

Lamotrigine metabolism may be substantially altered with concomitant administration of valproic acid and/or carbamazepine. Such alterations may require the adjustment of lamotrigine dose to ensure optimal treatment efficacy and safety. The extent of lamotrigine interactions was investigated dependent on age, gender, weight and dose of concomitant carbamazepine and/or valproic acid in 65 patients with epilepsy. Lamotrigine plasma steady-state oral clearance (CLss/F) and area under the curve (AUCss) were calculated from the dose of drug, average steady-state concentration (Css) and interval of administration. Multiple regression analysis was used for the identification and quantification of factors that influenced lamotrigine pharmacokinetics. Age and dose of carbamazepine and valproic acid had significant influence on lamotrigine CLss/F and AUCss. Carbamazepine was associated with a dose-dependent increase and valproic acid with a dose-dependent decrease of lamotrigine metabolism rate. The effect of carbamazepine was more pronounced. Younger patients were expected to metabolize lamotrigine more rapidly whereas overweight patients may be less susceptible to interactions. Gender had no influence on lamotrigine pharmacokinetics. The efficacy and safety of lamotrigine may be altered by concomitant administration of carbamazepine and valproic acid. The models developed may be useful for estimating doses of lamotrigine for individual patients to minimize clinically significant interactions. Therapeutic monitoring is advisable when those drugs are used concomitantly.

Evaluation of the Use of Static and Dynamic Models to Predict Drug-Drug Interaction and Its Associated Variability: Impact on Drug Discovery and Early Development

Simcyp, a population-based simulator, is widely used for evaluating drug-drug interaction (DDI) risks in healthy and disease populations. We compare the prediction performance of Simcyp with that of mechanistic static models using different types of inhibitor concentrations, with the aim of understanding their strengths/weaknesses and recommending the optimal use of tools in drug discovery/early development. The inclusion of an additional term in static equations to consider the contribution of hepatic first pass to DDIs (AUCR(hfp)) has also been examined. A second objective was to assess Simcyp's estimation of variability associated with DDIs. The data set used for the analysis comprises 19 clinical interactions from 11 proprietary compounds. Except for gut interaction parameters, all other input data were identical for Simcyp and static models. Static equations using an unbound average steady-state systemic inhibitor concentration (I(sys)) and a fixed fraction of gut extraction and neglecting gut extraction in the case of induction interactions performed better than Simcyp (84% compared with 58% of the interactions predicted within 2-fold). Differences in the prediction outcomes between the static and dynamic models are attributable to differences in first-pass contribution to DDI. The inclusion of AUCR(hfp) in static equations leads to systematic overprediction of interaction, suggesting a limited role for hepatic first pass in determining inhibition-based DDIs for our data set. Our analysis supports the use of static models when elimination routes of the victim compound and the role of gut extraction for the victim and/or inhibitor in humans are not well defined. A fixed variability of 40% of predicted mean area under the concentration-time curve ratio is recommended.

835 Exposure-Response Relationships in Telaprevir Combination Therapy in Treatment-NaïVE Genotype 1 Chronic HCV Patients

Introduction: Telaprevir (TVR) in combination with peginterferon alfa-2a (Peg-IFN) and ribavirin (RBV) was recently approved in the United States, Canada, Europe, and Japan for the treatment of genotype 1 chronic HCV infection. The relationship between drug exposure and safety and efficacy parameters is unclear. We evaluated relationships between efficacy and safety and concentrations of TVR, RBV, and Peg-IFN. Methods: Treatment-naive patients (N=472, ADVANCE/ILLUMINATE) who were assigned 12-weeks TVR combination therapy with 24or 48-weeks total PR and had PK data available were included. Using generalized linear modeling (logistic regression) and receiver operating characteristic (ROC) analyses, we investigated associations between drug exposures, eRVR, SVR, anorectal symptoms, and certain subsets of anemia (defined by DAIDS toxicity grading) and rash. Population PK model-predicted average steady-state TVR concentrations, the observed Week-4 RBV (plasma) concentrations, and observed Week-4 Peg-IFN (serum) concentrations were representative exposure measures. Results: eRVR and SVR weakly correlated with TVR, RBV, and Peg-IFN exposure. With increasing exposure, each drug exhibited a shallow, non-significant increase in eRVR and SVR probability. Anemia incidence during the TVR-phase correlated with TVR, RBV and Peg-IFN exposure, and correlated most strongly with RBV exposure. No drug exposures strongly correlated with rash or anorectal symptoms during the TVR-phase.

Effect of Menthol on Nicotine Pharmacokinetics in Rats After Cigarette Smoke Inhalation

The effect of menthol on nicotine disposition is important in understanding smoking behaviors among different racial groups. The present study was to evaluate whether menthol affects the pharmacokinetics of nicotine after cigarette smoke inhalation. Rats were exposed to mainstream smoke from either a nonmentholated or mentholated cigarette (1 puff/min for 10 min) using a smoke inhalation apparatus. For the multiple-cigarette smoke inhalation, rats received the smoke from either nonmentholated or mentholated cigarette (10 puffs) every 12 hr for a total of 17 cigarettes. Serial blood samples were collected during the 10-min inhalation phase for the single-cigarette smoke or the 17th cigarette inhalation and for 30 hr thereafter. Nicotine and its major metabolite cotinine were assayed by radioimmunoassay methods. Following single-cigarette smoke inhalation, mentholated cigarettes significantly decreased the mean peak concentrations of nicotine in plasma (C(max)) from 27.1 to 9.61 ng/ml and the total area under the plasma concentration-time curves (AUC) from 977 to 391 ng min/ml as compared with those after nonmentholated cigarette smoke inhalation. C(max) and AUC values for cotinine were also significantly reduced by menthol. Similarly after multiple smoke inhalation, C(max), AUC, and the mean average steady-state plasma concentration of nicotine as well as cotinine were significantly lower in mentholated cigarette inhalation. Interestingly, there was a significant increase in the cotinine to nicotine AUC ratio from 13.8 for the nonmentholated to 21.1 for the mentholated cigarette. These results suggest that menthol in mentholated cigarettes can substantially decrease the absorption and/or increase the clearance of nicotine.

Discreteness-induced concentration inversion in mesoscopic chemical systems

Molecular discreteness is apparent in small-volume chemical systems, such as biological cells, leading to stochastic kinetics. Here we present a theoretical framework to understand the effects of discreteness on the steady state of a monostable chemical reaction network. We consider independent realizations of the same chemical system in compartments of different volumes. Rate equations ignore molecular discreteness and predict the same average steady-state concentrations in all compartments. However, our theory predicts that the average steady state of the system varies with volume: if a species is more abundant than another for large volumes, then the reverse occurs for volumes below a critical value, leading to a concentration inversion effect. The addition of extrinsic noise increases the size of the critical volume. We theoretically predict the critical volumes and verify, by exact stochastic simulations, that rate equations are qualitatively incorrect in sub-critical volumes.

Phase 1 Study of UCN-01 in Combination with Perifosine in Patients with Relapsed and Refractory Acute Leukemias and High Risk Myelodysplastic Syndromes (MDS)

Abstract 1557 Introduction:The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway controls key cellular processes and is frequently activated in both acute and chronic myeloid leukemia (AML, CML) as well as high-risk MDS, thus representing an attractive therapeutic target. UCN-01 inhibits a number of serine-threonine kinases, including phosphatidylinositide-dependent kinase 1, which phosphorylates and activates Akt. Perifosine, an alkylphospholipid, targets the pleckstrin homology domain of Akt, thereby inhibiting its plasma membrane translocation and activation. Synergistic inhibition of Akt by UCN-01 and perifosine has been demonstrated in prostate and lung cancer cell lines (Clin Cancer Res 10: 5242, 2004). Methods:We conducted a Phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose of UCN-01 and perifosine, using a standard 3+3 dose escalation design. Patients (pts) >18 years with poor-risk, or relapsed/ refractory AML or acute lymphoblastic leukemia (ALL), CML in accelerated/blastic phase or MDS failing standard therapy, and peripheral blast count <30×109/l were eligible. Perifosine was administered on day (d)1 at 150 mg orally every 6 hours, then 100 mg daily from d2 continuously. UCN-01 was given as a 3-hour infusion on d4 at one of 3 dose levels (DL) (DL1 40/DL2 65/DL3 90 mg/m2). 28-day cycles were repeated depending on response/tolerability, with UCN-01 given at 50% dose. Antiemetic prophylaxis (perifosine) and hydration (UCN-01) were required. Results:Thirteen pts with AML (11), ALL (1), and MDS (1) were treated (DL1, n=6; DL2, n=4; DL3, n=3). Median age was 69 years (range, 20–85), 77% pts were male, and median number of prior treatments was 3 (range, 1–6). Nine of 11 AML patients had secondary (7)/therapy-related (2) disease, 4 had adverse and 5 intermediate karyotypes, and all were either primary refractory (4) or had first remission duration < 12 months (7). Pts received median 1 (range, 1–3) cycle of therapy. Five pts did not complete 1st cycle due to disease progression (n=3; DL1), cholecystitis/sepsis (n=1; DL3), or drug-related toxicity (n=1; DL3), and 4 received hydroxyurea temporarily to control increasing blast counts. The most frequent drug-related toxicities (NCI CTC v3) were grade (gr) 1/2 nausea and diarrhea (62% each), vomiting (54%), fatigue and hyperglycemia (31% each) anorexia, hypocalcemia and constipation (23% each), increased AST/ALT (15%), hypokalemia and hypotension (8% each). Few ≥gr 3 toxicities were seen, all at DL3: fatigue (gr 3), hyperglycemia (gr 4), hypokalemia (gr 3), pericarditis/tamponade/hypotension (gr 4) and respiratory distress (gr 4). MTD was therefore defined as 65 mg/m2 based on 2 pts with dose limiting toxicities at DL3. One AML pt (DL1) had disease stabilization for 3 cycles and one MDS pt (DL2) had improvement in neutrophil count. Given lack of sufficient evidence of clinical efficacy, the DL2 cohort was not expanded to 6 pts as planned. However, no gr 3/4 drug-related toxicities were observed in 10 pts treated at DL1/2. Pharmacodynamics:Western blot analysis did not consistently demonstrate appreciable direct Akt inhibition in ficolled blood/marrow mononuclear cells from 5 pts (DL1/2) on d4 (perifosine alone) or d21-28, however, a 38–74% reduction in phosphorylated ribosomal protein S6 in leukemic blasts from 3 pts on d4 was noted by intracellular flow cytometry, consistent with inhibition of signaling through the Akt downstream target p70S6 kinase. Pharmacokinetics:The average steady state concentration (Css) of perifosine was 4.75±2.53 μg/mL, consistent with published data (Eur J Cancer 38: 1615, 2002), with 1 pt having an unusually high Css of 9.25 μg/mL. The end-of-infusion concentration for UCN-01 was also consistent with published data (Clin Cancer Res 13: 2667, 2007), with average Cmax 13.2±0.424 μg/mL and 20.7±3.08 μg/mL at doses of 40 and 65 mg/m2, respectively. Conclusion:UCN-01 (40 or 65 mg/m2)/perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo and/or need to inhibit more than one signaling pathway to produce clinical response. Future studies with more potent Akt inhibitors should examine the validity of this approach in conjunction with pharmacodynamic monitoring. Disclosures:Carroll:Glaxo Smith Kline, Inc.: Research Funding; Sanofi Aventis Corporation: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding. Gojo:Keryx Inc.: Research Funding. Off Label Use: Neither UCN-01 nor perifosine have an approved indication.