Pharmacokinetic Potential Research Articles

Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects.

To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects. This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18-45years). In Period 1 (Days 1-12), siponimod was up-titrated from 0.25 to 2mg over 5days (Days 1-6) followed by 2mg once daily on days 7-12. In Period 2, siponimod 2mg qd was co-administered with rifampin 600mg qd (Days 13-24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC). Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6ng/mL) was achieved in 4h (median Tmax,ss; range, 1.58-8.00) and the geometric mean AUCtau,ss was 546h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7ng/mL and 235h × ng/mL, respectively; median Tmax remained unchanged (4h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L. The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.

Pharmaco‐parasitological evaluation of the ricobendazole plus levamisole nematodicidal combination in cattle

The goals of the current study were to evaluate the potential pharmacokinetic (PK) interactions and the clinical efficacy occurring after the subcutaneous (s.c.) administration of ricobendazole (RBZ) and levamisole (LEV) given both separately and co-administered to calves naturally infected with susceptible gastrointestinal nematodes. The clinical efficacy was shown in two seasons, winter and spring, with predominance of different nematode populations. Groups of 15 calves were treated with RBZ alone, LEV alone and RBZ+LEV combination, and an untreated group was kept as a Control. RBZ and LEV plasma concentrations were quantified by HPLC. The clinical efficacy was determined by the faecal egg count reduction test. RBZ and LEV have similar plasma persistence, being detected in plasma over 24hr post-treatment. No PK interactions were observed after the combined treatment, with similar PK parameters (p>.05) obtained for the single-drug and the combination-based strategy. In winter, the observed clinical efficacies were 96%, 99% and 100% for groups treated with RBZ, LEV and RBZ+LEV, respectively; however, in spring, the efficacies were 95%, 93% and 96% for the same groups. Remarkably, the combination was the only treatment that achieved 100% clinical efficacy against both Haemonchus spp and Ostertagia spp in winter; but the increased presence of Ostertagia spp. in spring (28% in untreated group) determined a tendency to reduced efficacies compared to winter time (only 10% of Ostertagia spp. in untreated group), even for the combined treatment. Overall, in a scenario where the nematode population is susceptible, the RBZ+LEV treatment may be a valid combination in cattle to delay the development of resistance, especially in winter when this combination achieved 100% of efficacy. Thus, selection of anthelmintic resistance will never occur. In fact, this is one of the greatest challenges for the whole cattle production system: to be one step ahead of anthelmintic resistance.

Resistant nematodes in cattle: Pharmaco-therapeutic assessment of the ivermectin- ricobendazole combination

Nematodicidal combinations have been proposed as a valid strategy to achieve effective nematode control in the presence of drug resistance. The goals of this study were: (1) to compare the clinical efficacy (therapeutic response) of ivermectin (IVM) and ricobendazole (RBZ) given subcutaneously either by separate or combined administration to calves naturally infected with gastrointestinal nematodes resistant to IVM, and (2) to evaluate the potential pharmacokinetic (PK) and/or pharmacodynamic (PD) interactions occurring after the co-administration of both anthelmintics. Sixty male calves naturally infected with gastrointestinal nematodes resistant to IVM were randomly allocated into four groups (n=15). Untreated control: animals not receiving anthelmintic treatment; IVM alone: animals treated with IVM by subcutaneous (SC) injection (0.2mg/kg); RBZ alone: animals received RBZ by the SC route (3.75mg/kg); IVM+RBZ: animals treated with IVM and RBZ (0.2 and 3.75mg/kg, respectively), by SC injection in two separates sites. Eight animals of each treated group were randomly selected to perform the PK study. Plasma samples were taken from those animals up to 28days post-treatment. IVM and RBZ plasma concentrations were quantified by HPLC. The therapeutic response was determined by faecal egg count reduction test (FECRT). The proportions of third-stage larvae (L3) recovered from coprocultures were used to calculate the efficacy against the main parasite genera. The daily total egg deposition for each experimental group was estimated. Similar pharmacokinetic trends were obtained for both IVM and RBZ allying the single-drug and the combined treatments, which indicates the absence of PK interactions between both anthelmintics. The observed overall clinical drug efficacies were 48% (IVM alone), 94% (RBZ alone) and 98% (IVM+RBZ). Haemonchus spp. and Cooperia spp. were recovered in the coproculture after IVM treatment, suggesting that resistance to IVM includes both genera. In fact, the efficacy against Cooperia spp. was 83% (IVM), 98% (RBZ) and 98% (IVM+RBZ), while the efficacy against Haemonchus spp. was 0% (IVM), 97% (RBZ) and 100% (IVM+RBZ). The combination was the only treatment that achieved 100% clinical efficacy against IVM-resistant Haemonchus spp. The total egg excretion was reduced to 49.9% (IVM alone group), 6.3% (RBZ alone group) and 1.8% (IVM+RBZ combined group) compared to the untreated control. Although the combined treatment did not significantly increase the overall clinical efficacy in the current natural field conditions, an additive effect was achieved against IVM-resistant nematodes. In fact, the combination obtained significantly higher efficacy against IVM-resistant Haemonchus spp. than RBZ alone. Additionally, the epidemiological relevance of the reduction in the number of eggs excreted following the combined treatment is not negligible and should be taken into account in future studies. Further work is required to understand the advantages of nematodicidal combinations in different natural anthelmintic resistance scenarios.

Abstract 2036: A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC)

Abstract Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + oral buparlisib (B) a pan-class I PI3K inhibitor, could provide a synergestic antitumor activity in trastuzumab resistant disease. LPT has been shown to be a potent CYP3A4 inhibitor which is also mainly involved in BKM120 metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of B and LPT. Methods: Trastuzumab-resistant HER2 + metastatic breast cancer (MBC) patients were treated with a continuous once daily dosing schedule of LPT + B. Dose levels [DL, LPT (mg)/B (mg)] ranged from 750/40 to 1,250/80. For PK analysis, 2 time point samples were collected on D1 and D8 and 10 time point samples were collected on D15 of cycle 1 for LPT and B assays. Plasma concentrations of B and LPT, were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modeled using a non linear mixed effect model program (Monolix version 4.3s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: 343 and 322 plasma concentrations were available for PK analysis of LPT and B respectively. A two-compartment open model adequately described B concentration versus time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance: CL, volume of distribution: V, inter-compartmental clearance: Q) except for absorption constant: Ka. The population PK parameters obtained for the structural model were: Ka = 0.985 h−1, CL/F = 10.5L/h, V1/F = 54.8 L, Q/F = 46.3 L/h, V2/F = 582 L. Mean AUC0-24h(CV%) values for B were 10130 (34%), 15450 (29%), and 20560 (38%) ng*hr/mL for 40 mg, 60 mg and 80 mg dose level respectively. A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL/F = 25.7 L/h, V/F = 291 L and the absorption constant, Ka = 0.214 h−1. B has no significant effect on the PK of LPT and vice versa. Conclusions: B AUC increased proportionally with increasing dose. LPT PK parameters are consistent with those already published. There is no significant evidence for drug-drug PK interaction between LPT and B. Intra-occasion variabilities will be discussed. Citation Format: François Lokiec, Anthony Goncalves, Fanny Bret, Jihane Pakradouni, Magali Provansal, Renaud Sabatier, Jean-Marc Extra, Carole Tarpin, Nicolas Isambert, Mario Campone, Keyvan Rezai. A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2036.

Abstract 2049: Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel

Abstract Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL. Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2). Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016). Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK. Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, François Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.

Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients.

A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose-lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability.

Pharmacokinetics of Selected Anticancer Drugs in Elderly Cancer Patients: Focus on Breast Cancer.

Background: Elderly patients receiving anticancer drugs may have an increased risk to develop treatment-related toxicities compared to their younger peers. However, a potential pharmacokinetic (PK) basis for this increased risk has not consistently been established yet. Therefore, the objective of this study was to systematically review the influence of age on the PK of anticancer agents frequently administered to elderly breast cancer patients. Methods: A literature search was performed using the PubMed electronic database, Summary of Product Characteristics (SmPC) and available drug approval reviews, as published by EMA and FDA. Publications that describe age-related PK profiles of selected anticancer drugs against breast cancer, excluding endocrine compounds, were selected and included. Results: This review presents an overview of the available data that describe the influence of increasing age on the PK of selected anticancer drugs used for the treatment of breast cancer. Conclusions: Selected published data revealed differences in the effect and magnitude of increasing age on the PK of several anticancer drugs. There may be clinically-relevant, age-related PK differences for anthracyclines and platina agents. In the majority of cases, age is not a good surrogate marker for anticancer drug PK, and the physiological state of the individual patient may better be approached by looking at organ function, Charlson Comorbidity Score or geriatric functional assessment.

A review of pharmacokinetic and pharmacodynamic interactions with antipsychotics.

Introduction: Antipsychotics are widely used and often in combination with other drugs, thereby frequently subjected to drug-drug interactions. This review will provide a summary of potential pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions associated with antipsychotic drugs.Methods: A literature search was conducted for clinically significant drug interactions with antipsychotics.Results: Most common PK drug interactions take place via the cytochrome P450 (CYP) system. PK profiles of first generation antipsychotics are inadequately studied; nevertheless most common drug interactions involve changes to their metabolic processes. Interactions with second generation antipsychotics are somewhat well-established, documented, and give some guidance for therapeutic treatment interventions. PD interactions occurring at the receptor level result in additive, synergistic, or antagonistic effects.Discussion: This review summarizes a collection of relevant literature of significant PK and PD interactions occurring with antipsychotics. The involvement of multiple CYP enzymes makes it more difficult to predict the extent of the interaction and clinicians should take into consideration the timeline when evaluating potential interactions.

Lack of Potential Pharmacokinetic and Pharmacodynamic Interactions Between Piragliatin, a Glucokinase Activator, and Simvastatin in Patients With Type 2 Diabetes Mellitus.

To evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD, glucose-lowering effect) interaction between simvastatin and piragliatin, both CYP3A substrates, 30 patients with type 2 diabetes mellitus participated in this open-label, randomized, 6-sequence, 3-way crossover (William's design) study. During 3 periods, patients were randomized to receive a single dose of 80 mg simvastatin alone, a single dose of 100 mg piragliatin alone, as well as single doses of 80 mg simvastatin and 100 mg piragliatin together. Primary PK and PD parameters were AUCs on dosing days. The ratio of geometric means (90% confidence intervals) of the AUCinf of piragliatin coadministered with simvastatin compared with piragliatin alone was 0.98 (0.92-1.05), whereas that of the AUCinf of simvastatin acid (active metabolite) coadministered with piragliatin compared with simvastatin alone, was 1.02 (0.90-1.16), suggesting lack of pharmacokinetic interaction between piragliatin and simvastatin. Piragliatin's glucose-lowering effect was not affected by coadministration of simvastatin. Overall, administration of piragliatin with simvastatin was without additional clinically relevant adverse effects as well as abnormality in laboratory tests, vital signs, and electrocardiogram parameters. Concomitant administration of simvastatin and piragliatin, both CYP3A substrates, has no clinically relevant effect on the pharmacokinetics of either piragliatin or simvastatin or on the pharmacodynamics for piragliatin.

Febuxostat Pharmacokinetic/Pharmacodynamic Bridging from Adults to Pediatrics for Effective Prophylaxis of Tumor Lysis Syndrome: From Florence to Floret Study

Background Febuxostat, a potent and selective xanthine oxidase inhibitor, showed a significantly superior serum uric acid (sUA) control during chemotherapy (CT) in comparison to Allopurinol (Spina M. et al, ASCO 2014 and Annals of Oncology in press) when given as 120 mg oral fixed daily dosed and has been recently approved in the European Union (EU) for the prevention and treatment of hyperuricemia in adult patients undergoing CT for hematologic malignancies (HM) at intermediate- high Tumor Lysis Syndrome (TLS) risk, with recognition of the high relevance of its clinical benefit. Some pediatric HM are highly prone to develop TLS; an age-appropriate drug formulation for TLS prophylaxis is lacking in this population, resulting in an unmet medical need that Febuxostat is going to address. The similarities between adult and pediatric patients in terms of TLS pathogenesis, clinical manifestations and current management allow using pharmacokinetic (PK) information to extrapolate clinical efficacy and safety from adult to pediatric patients, as well as within the different pediatric ages (EMEA/CHMP/EWP/147013/2004).Methods A phase I/II study (Floret) has been designed to explore the PK/pharmacodynamic (PK/PD) profile of Febuxostat in the pediatric population in comparison to adults. Febuxostat daily dose will be 120 mg for adolescents and adults with a lower 80 mg dose to be administered to adolescents only, to obtain confirmatory data on the optimal exposure in terms of safety and effectiveness compared to adults. Considering the difference in body size and organ maturation, the selected daily doses of Febuxostat to be tested in children aged 6 to 11 years are 40 and 60 mg. As the only approved strengths of Febuxostat in the EU are 80 and 120 mg, an age-appropriate 20 mg tablet formulation of Febuxostat is developed to ensure the adequate dosing in children. In accordance to the European Medicines Agency Guidelines CHMP/EWP/147013/2004 and CHMP/EWP/18599/2006, the choice of population PK analysis, using non-linear mixed effect models, is considered appropriate to obtain the necessary precision of PK parameters estimates for the comparability assessment between the groups of patients. The PD/efficacy measurement, namely the sUA area under curve from baseline to the evaluation visit, corresponding to the primary efficacy measure explored during the Florence study, a Phase III comparative trial in adults vs Allopurinol (Spina M et al, ASCO 2014), together with the exposure data will abridge the efficacy results from the Florence to the Floret study and will confirm that potential PK deviation, if any, is of no clinical relevance.Conclusion: The present PK/PD approach allows reducing the number of blood samples from each patient, in particular the lowest aged pediatric patients, while replacing a conventionally designed PK study and a robust sized Phase III study in pediatrics. By bridging PK/PD data, the Floret study not only will allow Febuxostat to rapidly address an unmet medical need in a vulnerable population, but it offers a model - whenever applicable - to be adopted to accelerate new drugs availability to the pediatric population while fully complying with regulatory requirements and minimize the number of patients in clinical trials. DisclosuresSpina:Menarini Ricerche SpA: Consultancy. Off Label Use: Febuxostat in pediatric Tumor lysis syndrome. Mazzei:Menarini Ricerche SpA: Employment. Baldini:Menarini Ricerche SpA: Employment. Pedretti:Menarini Ricerche SpA: Employment. Mezzalana:Menarini Ricerche SpA: Employment. Matera:Menarini Ricerche SpA: Employment. Manunta:Menarini Ricerche SpA: Employment. Calamai:Menarini Ricerche SpA: Employment. Scordari:Menarini Ricerche SpA: Employment. Scartoni:Menarini Ricerche SpA: Employment. Capriati:Menarini Ricerche SpA: Employment. Simonelli:Menarini Ricerche SpA: Employment.

Synergism in Pharmacokinetics of Retagliptin and Metformin Observed during Clinical Trials of their Combination Therapy

Purpose: To investigate the safety and potential pharmacokinetic (PK) interaction between retagliptin, a selective inhibitor of dipeptidyl peptidase-4, and metformin in healthy subjects.Methods: In open-label, randomized, three-period, three-treatment crossover studies, 15 subjects received 100 mg retagliptin, 1500 mg metformin or the combination. The area under the curve from the time of dosing to infinity (AUCinf) and the maximum observed plasma concentration (Cmax) of each drug were measured.Results: The combination of retagliptin and metformin did not result in clinically significant alterations in the pharmacokinetics of SP2086 or metformin. The AUCinf and Cmax of retagliptin co-administered with metformin were 16.49 and 25.88 % higher than for retagliptin alone, respectively, while the AUCinf of metformin co-administered with retagliptin was 22.06 % higher than for metformin alone. The 90 % confidence interval of both glucose-lowering drugs’ AUCinf and Cmax of the geometric mean ratios of SP2086 + metformin fell within the pre-specified interval of 80 - 125 %. No laboratory adverse conditions occurred during the study. Retagliptin appeared generally safe and well-tolerated when administered alone or in combination with metformin.Conclusion: The results may be an indication that no dose adjustments are likely to be required when retagliptin is given in combination with metformin.

Abstract CT302: Pharmacokinetics (PK) and safety of ARN-509 with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: ARN-509 and AA target the androgen axis via different mechanisms and may have complementary activity in mCRPC. ARN-509, a potent and selective androgen receptor (AR) antagonist, inhibits AR nuclear translocation and DNA binding without significant AR agonist properties (Clegg et al. Cancer Res. 2012). AA is the prodrug of abiraterone, which directly inhibits androgen biosynthesis. No overlapping toxicities are expected for the combination. This ongoing phase Ib study evaluates the potential PK drug-drug interaction and safety of ARN-509 in combination with AA + P. Methods: Pts had progressive mCRPC and ECOG score ≤ 2. Pts received AA (1000 mg/d) + P (5 mg BID) beginning on Cycle 1 Day 1 (C1D1) with the addition of ARN-509 (240 mg/d) on C1D8 in 28-day treatment cycles until disease progression or toxicity. Serial blood samples for PK analysis were collected on C1D7 and C2D8 for abiraterone analysis and on C2D8 for ARN-509 analysis. Primary objective: evaluate effect of ARN-509 on abiraterone PK. Secondary objective: evaluate safety of ARN-509 in combination with AA + P. Results: As of November 21, 2014, 28 pts have been enrolled. At baseline, the median age was 70 years (range: 49-83); median prostate-specific antigen was 56.8 μg/L (range: 4.1-2597.0 μg/L); bone, nodal, and visceral disease were present in 24 (86%), 17 (61%), and 8 (29%) pts; and 13 (46%) pts were pretreated with docetaxel, 11 (39%) with AA, and 12 (43%) with enzalutamide. 9 pts thus far completed 1 cycle, 6 completed 2 cycles, and 4 completed 3 cycles. 26 pts are continuing therapy. 10 pts were evaluable for PK assessment and 28 pts were evaluable for safety assessment. Most drug-related adverse events (AEs) were grade 1-2, and included fatigue (n = 5), diarrhea (n = 3), dysgeusia (n = 3), vomiting (n = 4), abdominal pain (n = 2), anorexia (n = 3), dyspepsia (n = 2), rash (n = 2) and nausea (n = 3). Grade 3 drug-related AEs included hyponatremia (n = 1), fatigue (n = 1), and increased alanine aminotransferase (n = 1), and were managed by drug interruption and supportive measures. Interim data indicate a small reduction in abiraterone PK exposure when AA + P is coadministered with ARN-509. PK of ARN-509 were consistent with historical data when ARN-509 was given as monotherapy. Conclusions: This ongoing phase Ib study (NCT02123758) indicates no clinically significant PK interaction between ARN-509 and AA + P. The combination is well tolerated in pts with mCRPC; interim AE data were consistent with those seen in the AA + P phase III trials (Fizazi et al. Lancet Oncol. 2012; Ryan et al. NEJM. 2013). These preliminary results justify further evaluation of the safety and efficacy of ARN-509 in combination with AA + P for mCRPC. Citation Format: Edwin M. Posadas, Kim N. Chi, Ronald de Wit, Maja JA de Jonge, Gerhardt Attard, Terence Friedlander, Margaret Yu, Peter Hellemans, Caly Chien, Charlene Abrams, Martha Gonzalez, Géralyn C. Trudel, Vijay Chauhan, Fred Saad. Pharmacokinetics (PK) and safety of ARN-509 with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT302. doi:10.1158/1538-7445.AM2015-CT302

Optimization of antibiotic therapy in the obese, critically ill patient

As the prevalence of obesity increases worldwide, clinicians will be more and more frequently confronted with obese, critically ill patients. Optimal administration of antibiotics is already a challenge in the critically ill patient because pharmacokinetics (PK) of antibiotics is often altered, and infections are more frequently caused by resistant pathogens than in the non-critically ill patient. Obesity per se may further alter the PK of antibiotics. This paper provides a narrative review of the potential PK changes of antibiotics in the obese, critically ill patient, and recommendations for optimal antibiotic therapy for the most frequently used antibiotics. However, these recommendations are essentially based on small sample-sized PK studies with no evaluation of outcome, and thus must be considered with caution. On one hand, critically ill patients may need higher than recommended regimens of β-lactams, linezolid, moxifloxacin, levofloxacin, tigecycline, and colistin; however, no further dose adjustment is necessary in obese, septic patients. Increased dosage regimens of β-lactams may be necessary only to treat obese, non-critically ill patients. On the opposite, dosage regimens should be based on total body weight for amikacin in patients with a body mass index (BMI) between 20 and 40 kg/m2, vancomycin, and daptomycin, and on adjusted body weight for ciprofloxacin, gentamycin, tobramycin, and amikacin in patients with a BMI greater than 40 kg/m2. Because of the lack of PK studies in this special patient population, and the large inter- and intraindividual PK drug variability in critically ill patients, we recommend therapeutic drug monitoring of all antibiotics administered, whenever possible, to optimize drug therapy.

Pharmacokinetic Interaction between Paclitaxel and Polyoxypregnanes

Polyoxypregnanes (POPs) as novel P-glycoprotein (P-gp) modulators were derived from a Chinese medicinal herb, Marsdeniae Tenacissimae Caulis., which has long been used in combination anti-cancer therapy. Our previous study demonstrated that three most abundant POPs in the herb can reverse P-gp-mediated paclitaxel resistance. The objective of present study was to investigate potential pharmacokinetic (PK) interaction between paclitaxel and POPs in Sprague-Dawley (SD) rats. POPs were orally pretreated by 8 h before intravenous paclitaxel administration to jugular vein- and bile duct-cannulated male SD rats. Paclitaxel and its metabolites were analyzed with LC-MS in plasma, feces, urine, bile and different tissues. POPs significantly increased the area under plasma concentration-time curve of paclitaxel by 1.5 folds, without changing Cmax and elimination half-life of paclitaxel. POPs did not dramatically affect paclitaxel metabolism and tissue distribution profile. The excretions of the intact paclitaxel in the urine and bile were significantly decreased in the presence of POPs. These results indicated that enhanced systemic exposure of paclitaxel might be due to the inhibitory effects of POPs on the P-gp-mediated excretion of paclitaxel. Our study revealed minor PK interaction between paclitaxel and POPs, and provided basis for a potential therapeutic benefit of this combination therapy for cancer patients.

A phase I clinical and pharmacokinetic study evaluating vinflunine in combination with epirubicin as first-line treatment in metastatic breast cancer

Vinflunine (VFL) is a bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with epirubicin (EPR) to establish the recommended dose (RD), to evaluate the safety and efficacy profiles and to investigate potential pharmacokinetic (PK) drug-drug interaction (DDI). Two schedules (day 1 every 3 weeks; days 1 and 8 every 3 weeks) were investigated as first-line chemotherapy of metastatic breast cancer patient. PK DDI was evaluated through population PK approaches. Thirty-nine patients received a total of 197 cycles of the VFL-EPR combination (median 6). The RDs were VFL 250 mg/m(2) + EPR 75 mg/m(2) every 3 weeks for schedule 1 and VFL 170 mg/m(2) + EPR 35 mg/m(2) every 3 weeks for schedule 2. The PK analysis demonstrated no clinically relevant mutual DDI between VFL and EPR. The main dose-limiting toxicity was neutropenia. The most frequent non-haematological adverse events were nausea, fatigue, constipation, vomiting, anorexia and stomatitis. Objective response rate was achieved in 45.9 % of the patients. VFL-EPR combination is feasible with manageable toxicity. The antitumour activity was promising and supports further evaluation.

Pharmacokinetic profile of micafungin when co-administered with amphotericin B in healthy male subjects

Micafungin and amphotericin B are antifungal agents with potent activity against a broad spectrum of fungal spp., including Candida and Aspergillus. The objective of this study was to evaluate the potential pharmacokinetic (PK) interaction of the two drugs in healthy subjects. PK were evaluated in healthy adults in an open-label, phase I clinical trial, following separate treatments with micafungin (200 mg; days 1 - 5) and conventional amphotericin B (0.25 mg/kg; days 8 - 13) alone, and following co-administration of both drugs (days 14 - 18). In 20 male subjects, systemic exposure to micafungin (measured using peak plasma micafungin concentration (Cmax) and area under the plasma micafungin concentration-time curve (AUC0-τ)) were similar following coadministration of micafungin and amphotericin B (day 18; Cmax 19.1 μg/mL, AUC0-τ 232 μg×h/mL) compared with administration of micafungin alone (day 5; Cmax 18.7 μg/mL, AUC0-τ 236 μg×h/mL), suggesting that administration of amphotericin B does not affect the PK of micafungin. The exposure to amphotericin B was ~ 30% greater following co-administration of both drugs (day 18; Cmax 704 μg/mL, AUC0-τ 9157 μg×h/mL) than after administration of amphotericin B alone (day 13; Cmax 621 μg/mL, AUC0-τ 7023 μg×h/mL). Concurrent treatment with micafungin and amphotericin B was less well tolerated than when either agent was administered alone. PK and safety-related observations during co-administration of micafungin and amphotericin B were considered to be a consequence of accumulation of amphotericin B to a steady state, indicating that co-administration of the two drugs does not affect the PK of micafungin.

Pharmacokinetic alteration of baclofen by multiple oral administration of herbal medicines in rats.

The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42–4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C max) and longer time to reach C max (T max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F urine). The absorption rate (K a) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

Absence of pharmacokinetic drug–drug interaction of pertuzumab with trastuzumab and docetaxel

Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

Demonstration of gender-specific variability in a pharmacokinetic (PK) analysis of the PERSIST-5 trial of adjuvant imatinib (IM) for patients with primary gastrointestinal stromal tumor (GIST) at significant risk of recurrence.

10538 Background: ThePERSIST-5 phase II trial is evaluating 5 years of adjuvant IM therapy in patients with resected GIST at significant risk of recurrence. This analysis studied the effect of chronic therapy on steady-state trough levels in patients who received IM for up to 24 months to evaluate potential PK variations. Methods: Eligible patients were adults with KIT+ primary GIST who were considered to be at significant risk for recurrence (primary tumor any site ≥2 cm andmitotic rate ≥5/50 high-power fields, or non-gastric primary GIST ≥5 cm) without metastases. R0 resection of primary GIST was performed ≤12 weeks prior to the first IM dose. Patients are to receive oral IM 400 mg/day for up to 5 years or until progression, relapse, or intolerance. Plasma samples for PK analysis were collected at 1, 4, 12, and 24 months. IM plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. Results: In-study assay performance (%CV) was ≤9.6% and bias was -1.3% to 5.2%. IM concentrations ranged from below quantifiable limits to 4798 ng/mL. After daily IM doses for up to 12 months (or 24 months in 3 patients), IM trough levels remained constant over time. The range of IM trough levels (mean ± SD) was 957 ± 750 ng/mL to 1219 ± 822 ng/mL at month 1, and 727 ± 430 ng/mL to 996 ± 405 ng/mL at month 12. Inter-patient variability was 40.7-78.4%. There was no significant difference in IM trough levels between months 1 and 4, 1 and 12, or 4 and 12. Trough levels did not significantly differ by location of GIST. Most notably, mean IM trough concentrations were on average ~33% higher in females vs males. Conclusions: In this study,IM trough levels remained relatively unaltered in patients with high-risk GIST who received adjuvant IM for 1 year. The 33% higher mean trough levels in females warrants further study for clinical decision making. Clinical trial information: NCT00867113. [Table: see text]

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

Introduction: The first-choice drug therapy in the management of type 2 diabetes is metformin. However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recently launched gliptin, with a unique pharmacokinetic (PK) profile characterized by negligible renal excretion and is now also available as a fixed-dose combination (FDC) with metformin.Areas covered: An extensive literature search was performed to analyze the potential PK and pharmacodynamic interactions between linagliptin and metformin. Linagliptin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug–drug interactions. Their coadministration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin-related gastrointestinal side effects.Expert opinion: The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes. That being said, the durability of the glucose-lowering effect of this combination needs to be further explored in long-term controlled trials.