Brendan M. Johnson

First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer

PurposeGSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295.Patients and methodsAdult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250xa0mg/m2. GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks.ResultsA total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190xa0mg/m2. Observed dose-limiting toxicities (all grade 3) were as follows: fatigue (nxa0=xa02, 5%), increased AST (nxa0=xa01, 2.5%), hypokalemia (nxa0=xa01, 2.5%), and hypoxia (nxa0=xa01, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event (nxa0=xa013; 33%). Gastrointestinal toxicities of diarrhea (nxa0=xa012, 31%), nausea (nxa0=xa08, 21%), and vomiting (nxa0=xa07, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250xa0mg/m2 and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9–11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250xa0mg/m2 dose level.ConclusionsThe novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.

Effect of food and gemfibrozil on the pharmacokinetics of the novel prolyl hydroxylase inhibitor GSK1278863

Anemia, a frequent complication of chronic kidney disease, is most commonly treated with recombinant human erythropoiesis‐stimulating agents. Oral administration of GSK1278863, a prolyl hydroxylase inhibitor, results in the accumulation of hypoxia‐inducible factor 1α, and stimulates erythropoiesis by triggering the pathways involved in innate hypoxia. In vitro biotransformation data indicate that GSK1278863 is primarily metabolized by CYP2C8. This study assessed the pharmacokinetics of single‐dose (100u2009mg) GSK1278863 administered alone, or co‐administered with a high‐fat/high‐calorie meal or steady‐state gemfibrozil (a strong CYP2C8 and OATP1B1 inhibitor). Co‐administration of single‐dose 100u2009mg GSK1278863 with a high‐fat/high‐calorie meal did not significantly affect the plasma exposure of GSK1278863 or its 6 predominant metabolites. Co‐administration of GSK1278863 with steady‐state gemfibrozil resulted in an 18.6‐fold increase in the area under the curve from time 0 to infinity (AUC(0–∞)) of GSK1278863. Additionally, the maximum plasma concentration (Cmax) and terminal elimination half‐life increased 3.92‐ and 3.70‐fold, respectively. The appearance of metabolites was delayed, and their Cmax and AUC(0–∞) were reduced by at least 90% and 62%, respectively. These findings indicate that GSK1278863 can be safely administered without regard to food. Until further studies with weaker CYP2C8 inhibitors are conducted, co‐administration of GSK1278863 with CYP2C8 inhibitors should be avoided.

Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone

IntroductionPharmacokinetic interactions between casopitant (a substrate and weak to moderate inhibitor of CYP3A), dexamethasone (a substrate and weak inducer of CYP3A), and ondansetron (a mixed CYP substrate) were evaluated in a two-part, three-period, single-sequence study in two groups of healthy subjects.Materials and methodsPart 1: subjects received oral casopitant (regimen A); oral dexamethasone and IV ondansetron (regimen B); and oral casopitant, a reduced dose of oral dexamethasone, and IV ondansetron (regimen C). Part 2: subjects received oral casopitant (regimen D); IV dexamethasone and oral ondansetron (regimen E); and oral casopitant, IV dexamethasone, and oral ondansetron (regimen F). Each regimen was separated by 14 days.ResultsCasopitant AUC in regimen C was increased 28% on day 1 but decreased 34% on day 3 compared to casopitant alone in regimen A. When given with casopitant and ondansetron in regimen C, dexamethasone AUC was 17% lower on dayxa01, but similar on dayxa03, compared to regimen B (representing dose-normalized increases in exposure of 39% and 108%, respectively). Ondansetron exposure was equivalent in regimens B and C. Casopitant AUC in regimen F was similar to regimen D on daysxa01 and 3. Dexamethasone AUC increased 21% when given with oral casopitant and oral ondansetron (regimen F compared to regimen E). Ondansetron exposure was equivalent in regimens E and F.ConclusionWhen repeat-dose oral dexamethasone is to be coadministered with oral casopitant, a reduction in dexamethasone dose may be considered; however, no change in casopitant dose is required. Ondansetron exposure was not affected by coadministration with casopitant.

Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia

PurposeEltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen.MethodsPharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10xa0days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated.ResultsThe PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50xa0years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy.ConclusionsSimulations indicated that eltrombopag administered 5xa0days before and 5xa0days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.

Population pharmacokinetics of intravenous ondansetron in oncology and surgical patients aged 1-48 months.

PurposeUntil recently, ondansetron was approved for the prevention of nausea and vomiting only in patients older than 2xa0years. However, as the use of ondansetron in patients younger than 2xa0years had been documented, characterization of ondansetron pharmacokinetics in this younger pediatric age group was warranted.MethodsThe pharmacokinetics of intravenously administered ondansetron were evaluated in oncology and surgical patients aged 1–48xa0months. Pooled data from 124 patients, including 745 pharmacokinetic samples, were analyzed using nonlinear mixed-effects modeling.ResultsOndansetron pharmacokinetics were described by a two-compartment model. Body-size effects on ondansetron disposition were accounted for via standard allometric relationships, normalized to 10.4xa0kg. A maturation process with a half-life of approximately 4xa0months was incorporated to describe a decrease in clearance (CL) in infants. Clearance [95% confidence interval (CI)] for a typical patient was 1.53 (1.34−1.78) L/h/kg0.75 with an interindividual variability of 56.8%. Ondansetron CL was reduced by 31%, 53%, and 76% for the typical 6-month-, 3-month-, and 1-month-old patient, respectively. Simulations showed that an ondansetron dose of 0.1xa0mg/kg in children younger than 6xa0months produced exposure similar to a 0.15-mg/kg dose in older children.ConclusionsThe population pharmacokinetic analysis of ondansetron allows for characterization of individual patients based on body weight and age. It is recommended that patients younger than 4xa0months receiving ondansetron be closely monitored.

A Phase 1 Trial of Eltrombopag in Patients Undergoing Stem Cell Transplantation after Total Body Irradiation

Stem cell transplantation can be associated with significant periods of thrombocytopenia, necessitating platelet transfusions and contributing to the risk of bleeding. Thrombopoietin receptor agonists have been shown to enhance platelet counts in other clinical settings, and so a phase 1 clinical trial was conducted to assess the safety, pharmacokinetics, and maximum tolerated dose of once-daily eltrombopag in patients undergoing stem cell transplantation with conditioning regimens containing total body irradiation ≥400 cGy. Eltrombopag was examined at dosage levels of 75, 150, 225, and 300 mg given orally once daily for 27 days, starting at 24 to 48 hours post-transplantation. Pharmacokinetic sampling was performed over a 24-hour period after the first dose of eltrombopag, as well as during the second week of treatment (steady-state). Nineteen patients were enrolled, 15 of whom completed protocol treatments. Three patients completed each dose level up to 225 mg, and 6 completed treatment at the highest dose of 300 mg. Four patients were replaced because drug compliance was <75% of planned doses. No dose-limiting toxicities were observed in this heterogeneous post-transplantation patient population. Common adverse events were related to standard stem cell transplantation. One episode of pulmonary embolus occurred 9 days after discontinuation of eltrombopag, and the only other thromboembolic episode was a grade 2 catheter-related clot. We conclude that up to 27 days of once-daily dosing of eltrombopag after stem cell transplantation is well tolerated.

Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron

ObjectiveThe objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron.Materials and methodsIn a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100xa0mg once daily for 3xa0days) or oral granisetron (2xa0mg once daily for 3xa0days) alone (period 1) and combined with oral casopitant, 150xa0mg dayxa01, 50xa0mg daysxa02 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on daysxa01 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort.ResultsThe largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on dayxa01 and 30% increase in Cmax on daysxa01 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%).ConclusionNone of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.

Effect of hepatic or renal impairment on the pharmacokinetics of casopitant, a NK-1 receptor antagonist

SummaryTwo studies were conducted in subjects with mild or moderate hepatic or renal impairment and subjects with normal organ function to evaluate the pharmacokinetics of casopitant and to assess its safety in these populations. A total of 26 subjects were enrolled in the hepatic impairment study and 18 subjects in the renal impairment study. All subjects received oral casopitant 100xa0mg once-daily for 5xa0days. Casopitant area under the concentration-time curve (AUC) increased 11% and 24% in subjects with mild or moderate hepatic impairment, respectively, on Dayxa01, compared with subjects with normal hepatic function; a similar increase was observed on Dayxa05. The AUC of the active major metabolite, GSK525060, was reduced 29% and 19% on Daysxa01 and 5, respectively, in subjects with moderate hepatic impairment, but not altered by mild hepatic impairment. Casopitant AUC increased 34% and 22% on Dayxa01 in subjects with mild or moderate renal impairment, respectively, and 28% and 11% on Dayxa05, respectively, compared with subjects with normal renal function. GSK525060 AUC was increased 17% and 24% on Daysxa01 and 5, respectively, in subjects with mild renal impairment; but did not significantly change in subjects with moderate renal impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Plasma protein binding of casopitant and GSK525060 was similar in all subjects. The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment was not evaluated.

Lack of effect of casopitant on the pharmacokinetics of docetaxel in patients with cancer.

PurposeThe neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel.MethodsFourteen cancer patients were enrolled in this phase 1, open-label, randomized, two-period crossover study. Intravenous (i.v.) docetaxel was coadministered with oral ondansetron and dexamethasone with (Regimen B) or without (Regimen A) 150xa0mg single-dose oral casopitant.ResultsThe geometric least-squares mean Regimen B: Regimen A ratios (90% confidence interval) for docetaxel maximum plasma concentration and area under the concentration–time curve from time 0 extrapolated to infinity were 0.97 (0.83, 1.12) and 1.06 (0.94, 1.19), respectively. Coadministration of casopitant and docetaxel was well tolerated, with adverse event profiles and absolute neutrophil count nadirs similar for both treatments.ConclusionsCmax and AUC of docetaxel were similar when given as monotherapy or when given in combination with casopitant. Likewise, absolute neutrophil count nadirs were similar for docetaxel alone or docetaxel with casopitant.

A pharmacokinetic, pharmacodynamic, and safety study of intravenous cyclophosphamide with an oral casopitant antiemetic regimen in cancer patients

Casopitant is a potent and selective neurokinin‐1 receptor antagonist formerly under development for a number of indications, including the treatment of chemotherapy‐induced nausea and vomiting. This study was an open‐label, randomized, multi‐center, two‐period crossover casopitant–cyclophosphamide interaction study. Subjects were cancer patients receiving cyclophosphamide based chemotherapy. The objectives of the study were to assess the effect of 3‐day, repeat‐dose, 150u2009mg oral casopitant on the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (white blood cell count) of single‐dose IV cyclophosphamide. PK data from 14 evaluable subjects showed the geometric least‐squares mean ratios (90% CI) for cyclophosphamide and the metabolite 4‐hydroxycyclophosphamide AUC (with:without casopitant) were 1.03 (0.975, 1.09) and 0.948 (0.835, 1.08), respectively. Administration of casopitant was well tolerated and did not impact the safety profile of the treatment regimen. Casopitant did not affect the expected bone marrow toxicity of cyclophosphamide. Co‐administration of 150u2009mg oral casopitant with single‐dose IV cyclophosphamide did not appear to result in a clinically relevant change in cyclophosphamide or 4‐hydroxycyclophosphamide exposure or safety.