Background: Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A ...biodegradable, long‐acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence.
Methods: The single‐ and multiple‐dose safety and pharmacokinetics of a long‐acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n=28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long‐acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n=14) received oral naltrexone 50 mg daily for 5 days, followed by IM long‐acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7‐day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6β‐naltrexol.
Results: After a single IM injection of long‐acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half‐lives for naltrexone and 6β‐naltrexol ranged from 5 to 7 days. Exposure to 6β‐naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred.
Conclusions: This study demonstrated that the long‐acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first‐pass metabolism and changes the exposure ratio of 6β‐naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long‐acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.
Injectable extended-release naltrexone (XR-NTX; Vivitrol) has recently been approved for the treatment of alcohol dependence. A population pharmacokinetic (PPK) analysis examined the possibility of ...altered pharmacokinetics for naltrexone and its primary metabolite, 6beta-naltrexol, in subpopulations with a potential for alcohol-dependence treatment.
Data from four clinical studies of XR-NTX were pooled. Absorption was modeled as a sequential release in three phases. The pharmacokinetics of naltrexone and 6beta-naltrexol were modeled as one-compartment disposition submodels, parameterized in terms of clearance (CL) and volume of distribution (V). The impact of age, weight, gender, race, hepatic function, renal function, smoking, and alcohol/opioid dependence on PPK parameter estimates was analyzed.
Plasma concentrations were available from 453 subjects. More than half of the subjects (59%) were alcohol dependent, and 27% were dependent on both alcohol and opioids. Naltrexone CL (140 L/h) and V (38,300 L) were dependent on weight (changes of 0.548 L/h/kg and 0.655 L/kg, respectively) and were 23% and 35% higher, respectively, in subjects with alcohol and/or opioid dependence than in healthy subjects. Naltrexone CL also was dependent on age (-0.108 L/h/year); 6beta-naltrexol CL (65.1 L/h) was dependent on creatinine CL (0.229 L/h/ml/minute) and alkaline phosphatase (-0.130 L/h/IU/L), and was increased by 18% in smokers and in alcohol- and/or opioid-dependent subjects.
Although statistically significant covariate-parameter relationships were identified, they were not considered clinically meaningful, suggesting that dosing adjustments of XR-NTX based on weight, age, gender, health status, smoking status, creatinine CL, and hepatic function differences should not be necessary.
Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting ...the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.
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•IPI-145 is a potent, oral class I PI3K inhibitor targeting PI3K-δ and PI3K-γ•IPI-145 inhibits adaptive and innate immune function•IPI-145 is orally active in therapeutic models of inflammatory and autoimmune disease•IPI-145 has therapeutic potential for autoimmune disease and hematopoietic cancers
Winkler et al. explore the therapeutic value of combined PI3K-δ and PI3K-γ blockade and describe a potent, oral PI3K-δ and PI3K-γ inhibitor, IPI-145. IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models.
Long‐acting naltrexone is an extended‐release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and ...moderate hepatic impairment on naltrexone pharmacokinetics following long‐acting naltrexone 190‐mg administration was assessed. Subjects with mild (Child‐Pugh grade A) and moderate (Child‐Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6β‐naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6β‐naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC0‐∞) of naltrexone and 6β‐naltrexol was similar across all groups. The long apparent half‐lives of naltrexone and 6β‐naltrexol (5–8 days) were attributed to the slow release of naltrexone (long‐acting naltrexone exhibits absorption rate‐limited elimination or “flip‐flop” kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long‐acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.
To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical ...entity that inhibits the Hedgehog pathway (HhP).
Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day -7 and day 22 of cycle 1.
Ninety-four patients (32F, 62M; ages, 39-87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (T(max) = 2-8 hours) and a terminal half-life (t(1/2)) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg.
IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor-naïve patients with BCC.
Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of ...gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS).
IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging.
Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST.
In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.
Objective To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC). Methods A single-arm trial was conducted in 2 ...cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout. Results A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively. Conclusion Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.
Vixotrigine is a voltage‐ and use‐dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is ...metabolized primarily via uridine diphosphate‐glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first‐line treatment for trigeminal neuralgia. We conducted a double‐blind, randomized, placebo‐controlled, parallel‐group, single‐center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1‐3 and 200 mg twice a day, days 4‐21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole‐blood samples were collected for PK assessment. Statistical analyses were performed on the log‐transformed PK parameters area under the concentration‐time curve within a dosing interval (AUC0‐tau) and maximum observed concentration (Cmax) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0‐tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0‐tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0‐tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.
Introduction: Signaling via PI3K-δ and PI3K-γ is essential for both normal and malignant B-cell and T-cell proliferation, survival, and migration. PI3K-δ and PI3K-γ have distinct and complimentary ...effects on malignant B-cells and nonmalignant immune cells important in tumor immunity and the tumor microenvironment. Duvelisib (IPI-145) is a novel targeted oral PI3K-δ,γ inhibitor in development for the treatment of hematologic malignancies. An ongoing Phase 1 study has demonstrated substantial clinical activity in patients (pts) with advanced hematologic malignancies, including pts with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL).
Methods: This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of duvelisib administered continuously in 28-day cycles. The optimal biological dose (supported by pharmacodynamic studies and clinical activity) selected for chronic administration in iNHL (25 mg BID) was further evaluated in expansion cohorts in R/R iNHL pts while additional testing up to the MTD (75 mg BID) was pursued to further characterize safety and activity. iNHL clinical responses were evaluated based on revised IWG (2007) criteria with additional criteria for Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) where appropriate.
Results: A total of 32 pts with R/R iNHL (follicular lymphoma, marginal zone lymphoma and WM/LPL) were enrolled, including 16 pts dosed at 25 mg BID (1 pt received 15 mg BID). The median age was 65 years range: 37-78 and 56% were male. Nineteen (59%) pts had ≥3 prior systemic therapies and 34% were <6 months from their most recent therapy. Baseline cytopenias ≥Grade 1 at study entry were: anemia n=19 (61%), neutropenia n=8 (26%), and thrombocytopenia n=8 (26%).
The R/R iNHL pts received duvelisib at doses ranging from 15 mg BID to 75 mg BID. Pharmacokinetic data demonstrated that exposure (AUC and Cmax) increased across the dose range evaluated. There was evidence of pharmacodynamic modulation based on reductions in serum cytokines and chemokines known to support the malignant B-cell microenvironment. Despite increasing exposure above 25 mg BID, cytokine and chemokine reductions were similar at doses of 25 mg BID or higher.
Consistent with the pharmacodynamic observations, clinical activity was observed in R/R iNHL pts at all doses of duvelisib evaluated (15 mg BID to 75 mg BID). In the efficacy evaluable population (n=31), the ORR was 65% with a best response of 5 complete responses (CR) (all follicular), 14 partial responses (PR), 1 minor response (MR), 9 stable disease (SD) and 2 progressive disease (PD), and with a median time to response of 1.8 months. For the subset of 15 evaluable pts treated at 25 mg BID (1 pt received 15 mg BID), the ORR was 73% (including 4 CRs). This pt subset has received a median of 11 treatment cycles (range: 1.1-28.7), with 47% (7/15) remaining on long-term treatment (1 to >2 years).
The overall safety profile has been consistent across the range of doses studied in R/R iNHL pts (median of 6 treatment cycles range: 0.1-28.7). The majority of adverse events (AEs) were Grade 1-2, reversible and/or clinically manageable. The most common ≥Grade 3 treatment-emergent AEs (≥15%, all causality) were ALT/AST increase (n=13 41%) with a median time to occurrence of 50 days (range: 5-448), and diarrhea (n=7 22%) with a median time to occurrence of 124 days (range: 36-434). In addition, transient ≥Grade 3 neutropenia was reported in 10 pts (31%), including 6 pts who entered the study with baseline neutropenia. The most common reasons for treatment discontinuation included AEs (10/32, 31%) and disease progression (7/32, 22%).
Conclusions: Duvelisib (IPI-145), a novel oral PI3K-δ,γ inhibitor, appears generally well tolerated with an acceptable safety profile across the dose range evaluated. Evidence of clinical activity in pts with R/R iNHL was observed with an ORR of 65% including CRs in 25% (5/20) of responding pts. Based on these promising results which suggest a positive benefit-risk in this pt population, registration trials in pts with iNHL evaluating 25 mg BID as a monotherapy or in combination with rituximab are ongoing or planned, respectively.
Flinn:Infinity Pharmaceuticals: Consultancy. Off Label Use: This is an investigational drug not FDA approved.. Oki:Infinity Pharmaceuticals Inc: Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum-Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Foss:Eisai, Celgene, Seattle Genetics: Consultancy, Research Funding, Speakers Bureau. Sweeney:Infinity Pharmaceuticals: Employment. Allen:Infinity Pharmaceuticals: Employment. Douglas:Infinity Pharmaceuticals, Inc.: Employment. Steelman:Infinity Pharmaceuticals: Employment. Dunbar:Infinity Pharmaceuticals Inc: Employment. Stern:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals: Employment. Kahl:Infinity Pharmaceuticals Inc: Consultancy, Research Funding.
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