The Experts below are selected from a list of 1959 Experts worldwide ranked by ideXlab platform
Zhanna Kobalava - One of the best experts on this subject based on the ideXlab platform.
-
pharmacokinetics and safety of the anti human cytomegalovirus drug letermovir in subjects with Hepatic Impairment
2017Co-Authors: Dirk Kropeit, Hanspeter Stobernack, Holger Zimmermann, David Mccormick, Katharina Erbzohar, Valentin S Moiseev, Zhanna Kobalava, Helga RubsamenschaeffAbstract:Aims Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of Hepatic Impairment on letermovir pharmacokinetics. Methods Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with Hepatic Impairment and healthy matched controls. For 8 days, subjects with moderate Hepatic Impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with Severe Hepatic Impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. Results For subjects with moderate Hepatic Impairment, maximal observed concentration at steady state (Css,max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with Severe Hepatic Impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Conclusions Moderate Hepatic Impairment increased exposure to letermovir <2-fold, while Severe Hepatic Impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with Hepatic Impairment.
-
a phase 1 open label single dose study of the pharmacokinetics of buparlisib in subjects with mild to Severe Hepatic Impairment
2016Co-Authors: Denes Csonka, Katharine Hazell, Edward Waldron, Sebastien Lorenzo, Vincent Duval, Lucia Trandafir, Zhanna KobalavaAbstract:The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to Severe Hepatic Impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞] and Cmax) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0–1.3 h). Buparlisib exposure (AUC∞) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or Severe (GMR 1.20; 90%CI 0.84, 1.72) Hepatic Impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the Severe group (0.21) than all other groups (0.17), subjects with Severe Hepatic Impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC∞ 1.52; 90%CI 1.09, 2.13; Cmax 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate Hepatic Impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with Severe Hepatic Impairment.
-
pharmacokinetics of serelaxin in patients with Hepatic Impairment a single dose open label parallel group study
2015Co-Authors: Zhanna Kobalava, Iris Rajman, Jasna Canadi, Yinuo Pang, Svetlana Villevalde, Yulia Kotovskaya, Holger Hinrichsen, Andreas Zaehringer, Marc Petersensylla, Marion DahlkeAbstract:Aims Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with Hepatic Impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. Methods This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg−1 day−1) between patients with mild, moderate or Severe Hepatic Impairment (Child–Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration–time curve AUC(0–48 h) and AUC(0–∞) and serum concentration at 24 h post-dose (C24h)] were compared between each Hepatic Impairment group and healthy controls. Results A total of 49 subjects (including 25 patients with Hepatic Impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12–24 h and then declined following completion of infusion, with a mean terminal half-life of 7–8 h. All PK parameter estimates were comparable between each group of patients with Hepatic Impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. Conclusions The PK and safety profile of serelaxin were not affected by Hepatic Impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with Hepatic Impairment.
Karthik Venkatakrishnan - One of the best experts on this subject based on the ideXlab platform.
-
pharmacokinetics of the investigational aurora a kinase inhibitor alisertib in adult patients with advanced solid tumors or relapsed refractory lymphoma with varying degrees of Hepatic dysfunction
2019Co-Authors: Xiaofei Zhou, John Sarantopoulos, John Nemunaitis, Michael Bargfrede, Andreas Muehler, Craig A Lockhart, Lakshmi Rangachari, Karthik VenkatakrishnanAbstract:This clinical trial was designed to evaluate the effect of moderate or Severe Hepatic Impairment on the single-dose pharmacokinetics (PK) of the investigational anticancer agent, alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal Hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate Hepatic Impairment (1.5 × ULN 3 × ULN, with any ALT), received a single 50-mg oral dose of alisertib. Blood samples for PK were collected up to 168 hours postdose. Predose samples were also used to assess alisertib plasma protein binding. Patients could continue to receive alisertib for 7 days in 21-day cycles (50, 30, or 10 mg twice daily for normal Hepatic function, moderate Hepatic Impairment, and Severe Hepatic Impairment, respectively). Alisertib was approximately 99% protein bound in all Hepatic function groups. Alisertib exposure was similar in moderate and Severe Hepatic Impairment groups, but higher than the normal Hepatic function group. The geometric least-squares mean ratios (90% confidence intervals) for unbound alisertib area under the curve extrapolated to infinity for moderate/Severe Impairment groups versus the normal Hepatic function group was 254% (184%, 353%). Patients with moderate or Severe Hepatic Impairment have approximately 150% higher unbound alisertib exposures compared with patients with normal Hepatic function. An approximately 60% reduction of the starting dose of alisertib in patients with moderate/Severe Hepatic Impairment is recommended based on pharmacokinetic considerations.
-
Mass balance, routes of excretion, and pharmacokinetics of investigational oral [^14C]-alisertib (MLN8237), an Aurora A kinase inhibitor in patients with advanced solid tumors
2019Co-Authors: Xiaofei Zhou, Claudio Dansky Ullmann, Sandeepraj Pusalkar, Swapan K Chowdhury, Shawn Searle, Karthik VenkatakrishnanAbstract:Aims This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics and safety of the investigational aurora A kinase inhibitor, alisertib, in three patients with advanced malignancies. Methods Part A; patients received a single 35-mg dose of [^14C]-alisertib oral solution (~80 μCi total radioactivity [TRA]). Serial blood, urine, and fecal samples were collected up to 336 h post-dose for alisertib mass balance and pharmacokinetics in plasma and urine by liquid chromatography–tandem mass spectrometry, and mass balance/recovery of [^14C]-radioactivity in urine and feces by liquid scintillation counting. Part B; patients received non-radiolabeled alisertib 50 mg as enteric-coated tablets twice-daily for 7 days in 21-day cycles. Results In part A, absorption was fast (median plasma T_max, 1 h) for alisertib and TRA. Mean plasma t_1/2 for alisertib and TRA were 23.4 and 42.0 h, respectively. Mean plasma alisertib/TRA AUC_0–inf ratio was 0.45, indicating presence of alisertib metabolites in circulation. Mean TRA blood/plasma AUC_0–last ratio was 0.60, indicating preferential distribution of drug-related material in plasma. On average, 87.8% and 2.7% of administered radioactivity was recovered in feces and urine, respectively (total recovery, 90.5% by 14 days post-dose). In part B, patients received a median 3 cycles of alisertib. The most common any-grade adverse events were fatigue and alopecia. Conclusions Findings suggest that alisertib is eliminated mainly via feces, consistent with Hepatic metabolism and biliary excretion of drug-related material. Further investigation of alisertib pharmacokinetics in patients with moderate-Severe Hepatic Impairment is warranted to inform dosing recommendations in these patient populations.
-
Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor
2019Co-Authors: Neeraj Gupta, Richard Labotka, R. Donald Harvey, Michael J. Hanley, Karthik VenkatakrishnanAbstract:Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal Impairment, or mild Hepatic Impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with Severe renal Impairment, end-stage renal disease requiring dialysis, or moderate-to-Severe Hepatic Impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib. Drug–drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in ixazomib exposure, supporting the recommendation to avoid concomitant administration of ixazomib with strong CYP3A inducers. Exposure–response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit–risk profile for the approved dose and regimen of weekly ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.
-
pharmacokinetics of ixazomib an oral proteasome inhibitor in solid tumour patients with moderate or Severe Hepatic Impairment
2016Co-Authors: Neeraj Gupta, Karthik Venkatakrishnan, Michael J. Hanley, Raymond P. Perez, Robin E. Norris, John Nemunaitis, Huyuan Yang, Gerald Steven Falchook, Mark G Qian, Richard LabotkaAbstract:Aim The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or Severe Hepatic Impairment, to provide posology recommendations. Methods Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal Hepatic function, moderate Hepatic Impairment or Severe Hepatic Impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. Results Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and Severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/Severe Hepatic Impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal Hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. Conclusions In patients with moderate/Severe Hepatic Impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal Hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or Severe Hepatic Impairment.
-
A Phase 1 Study to Assess Pharmacokinetics (PK) and Safety of Ixazomib, an Oral Proteasome Inhibitor, in Patients with Moderate or Severe Hepatic Impairment
2015Co-Authors: Neeraj Gupta, Karthik Venkatakrishnan, Michael J. Hanley, Raymond P. Perez, Robin E. Norris, John Nemunaitis, Huyuan Yang, Gerald Steven Falchook, Richard LabotkaAbstract:Background The investigational oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in patients with multiple myeloma and amyloidosis. Metabolism is the major mechanism of ixazomib clearance; accordingly, Hepatic Impairment may increase ixazomib exposures. PK and safety data suggested no clinically relevant PK alterations in patients with mild Hepatic Impairment (Gupta et al BJCP 2015). This study (NCT01912222) was performed to characterize the PK of ixazomib in patients with moderate or Severe Hepatic Impairment, as defined by the NCI Organ Dysfunction Working Group, to develop dosing recommendations for these specific patient populations. Methods Eligible adults had advanced malignancies for which no further effective therapy was available. Twelve PK-evaluable patients were planned to be enrolled to each of the normal (N), moderate (M) or Severe (S) Hepatic Impairment groups. Patients received a single dose of ixazomib on day 1; those in the N, M, and S groups received ixazomib 4, 2.3, and 1.5 mg, respectively. Blood samples were collected at multiple time points for 15 days after dosing to characterize single dose PK (18 samples in total, 0.5-8 hr on day 1, days 2-8, days 11, 12, and 15). After completion of PK sampling, patients could continue on the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Geometric mean ratios and 90% CIs of unbound dose-normalized (DN) PK parameters in the Hepatic Impairment vs normal groups were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03. Results Forty-eight patients were enrolled (13, 15, and 20 patients to the N, M, and S groups, respectively); 32 were Caucasian, 10 African American, 2 Asian, and 4 other. Mean age was 56 years (range 24-83), mean weight 76 kg (range 43-127), and mean body surface area 1.9 m2 (range 1.4-2.5); 28 (58%) were male. The most common cancers were hepatocellular carcinoma (21%) and colorectal carcinoma, with or without liver metastases (10%). All patients in the S group had liver dysfunction due to primary or metastatic tumors. Forty-three patients had reportable PK parameters (Cmax or AUC) and were PK-evaluable (12 N, 13 M, 18 S). PK parameters are reported in the Table. Ixazomib was rapidly absorbed in all 3 Hepatic function groups examined, with a median Tmaxof 0.95-1.5 hours. Ixazomib was highly bound to plasma proteins with a similar mean fraction bound (~99%) in all 3 groups. Only 1 (2%) patient continued on study for more than 3 cycles (endometrial carcinoma, 10 cycles). Discontinuations were due to progression (75% of discontinuations), TEAEs or death related to progression. The most common TEAEs were nausea (38%), fatigue (31%), peripheral edema (31%), vomiting (27%), dyspnea (23%), decreased appetite (21%), and hyperbilirubinemia (21%). Most patients (77%) had a grade ≥3 TEAE, including 15% with a grade ≥3 study drug-related TEAE (dehydration [6%], fatigue [4%], anemia [2%], and fall [2%]); no patient had a study drug-related grade 4 TEAE. There were 14 on-study deaths, all of which were considered related to disease progression. Conclusions Unbound systemic exposures of ixazomib were 27% higher in patients with moderate or Severe Hepatic Impairment versus those in patients with normal Hepatic function. A reduced starting ixazomib dose of 3 mg is recommended for patients with moderate or Severe Hepatic Impairment. Disclosures Gupta:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Off Label Use: Investigational proteasome inhibitor ixazomib. Hanley:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Perez:Dompe: Research Funding; Eli Lilly: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Immunogen: Research Funding; Bristol Meyers Squibb: Research Funding; Agensys: Research Funding; PRA: Consultancy; Tetralogics: Research Funding. Norris:Nektar Pharmaceuticals: Consultancy. Yang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Falchook:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.
Helga Rubsamenschaeff - One of the best experts on this subject based on the ideXlab platform.
-
pharmacokinetics and safety of the anti human cytomegalovirus drug letermovir in subjects with Hepatic Impairment
2017Co-Authors: Dirk Kropeit, Hanspeter Stobernack, Holger Zimmermann, David Mccormick, Katharina Erbzohar, Valentin S Moiseev, Zhanna Kobalava, Helga RubsamenschaeffAbstract:Aims Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of Hepatic Impairment on letermovir pharmacokinetics. Methods Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with Hepatic Impairment and healthy matched controls. For 8 days, subjects with moderate Hepatic Impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with Severe Hepatic Impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. Results For subjects with moderate Hepatic Impairment, maximal observed concentration at steady state (Css,max) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with Severe Hepatic Impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. Conclusions Moderate Hepatic Impairment increased exposure to letermovir <2-fold, while Severe Hepatic Impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with Hepatic Impairment.
Denes Csonka - One of the best experts on this subject based on the ideXlab platform.
-
macitentan for the treatment of portopulmonary hypertension portico a multicentre randomised double blind placebo controlled phase 4 trial
2019Co-Authors: Olivier Sitbon, Emmanuelle Cottreel, Marius M Hoeper, Nicolas Martin, Jaume Bosch, Denes Csonka, Pascal De Groote, L Savale, Michael J KrowkaAbstract:Summary Background No dedicated randomised clinical trials have evaluated therapies for pulmonary arterial hypertension in patients with portopulmonary hypertension. The endothelin receptor antagonist macitentan has demonstrated long-term efficacy in pulmonary arterial hypertension with a good Hepatic safety profile. We aimed to evaluate efficacy and safety of macitentan in patients with portopulmonary hypertension. Methods PORTICO was a phase 4 study done in 36 centres in seven countries, consisting of a 12-week double-blind period (randomly assigned 1:1 to macitentan 10 mg or placebo once daily) followed by a 12-week open-label period. Adults (≥18 years) with portopulmonary hypertension, a 6-minute walk distance of 50 m or more, and with pulmonary vascular resistance of 320 dyn·s·cm−5 or more without Severe Hepatic Impairment (Child-Pugh class C or model for end-stage liver disease score ≥19) were eligible. The primary endpoint was pulmonary vascular resistance at week 12, expressed as ratio of baseline in the full analysis set. Safety was assessed throughout. This trial is registered at ClinicalTrials.gov , number NCT02382016 . Findings Between June 23, 2015, and July 28, 2017, 85 patients were randomly assigned to macitentan (n=43) or placebo (n=42). At baseline, 54 (64%) were receiving background therapy for pulmonary arterial hypertension. Most patients were WHO functional class II (50, 59%) or III (33, 39%) with a mean 6-minute walk distance of 384·5 m (SD 103·9). At week 12, the geometric mean ratio of baseline pulmonary vascular resistance was 0·63 (95% CI 0·58–0·67) in the macitentan group and 0·98 (95% CI 0·91–1·05) in the placebo group, corresponding to a ratio of geometric mean for pulmonary vascular resistance of 0·65 (95% CI 0·59–0·72, p Interpretation Macitentan significantly improved pulmonary vascular resistance in portopulmonary hypertension patients, with no Hepatic safety concerns. Funding Actelion Pharmaceuticals Ltd.
-
p17 pharmacokinetics of macitentan in patients with portopulmonary hypertension findings from the portico sub study
2018Co-Authors: Colin Church, Michael J Krowka, Emmanuelle Cottreel, Marius M Hoeper, Nicolas Martin, Jaume Bosch, Denes Csonka, Olivier SitbonAbstract:Introduction and objectives Macitentan is an endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH). The PORTICO trial (NCT02382016) explored the efficacy and safety of macitentan in 85 patients with portopulmonary hypertension (PoPH), a population of patients in whom PAH is a complication of portal hypertension. In PORTICO, macitentan significantly improved pulmonary vascular resistance (PVR; primary endpoint; 35% reduction vs placebo), mean pulmonary artery pressure (mPAP) and cardiac index, with no Hepatic safety concerns. The PORTICO pharmacokinetic (PK) sub-study explored the PK of macitentan and its active metabolite in patients with PoPH. Methods PORTICO consisted of a 12 week randomised, double-blind, placebo-controlled treatment period, followed by a 12 week open-label treatment period during which all patients?received macitentan. Patients were aged ≥18 years and diagnosed with PoPH (PVR >320 dyn/sec/cm5; mPAP ≥25 mmHg; pulmonary artery wedge pressure or left ventricular end diastolic pressure ≤15 mmHg), without Severe Hepatic Impairment (defined as Child-Pugh class C or model for end-stage liver disease score ≥19). In the PK sub-study, a 24 hour PK profile was recorded at steady-state?after ≥4 weeks of open-label treatment with once-daily macitentan 10 mg. The PK analysis included patients who provided sufficient plasma samples for PK profile evaluation of macitentan and its active metabolite. Results The PK sub-study was performed in ten patients; seven were male and the mean (standard deviation [SD]) age was 54.9 (8.6) years. The PK results for macitentan and its active metabolite in PORTICO were comparable with those reported in the PK sub-study of the Phase III SERAPHIN trial (NCT00660179) in patients with other forms of PAH (n=20) (table 1). Conclusion The results from the PORTICO PK sub-study suggest that the steady-state exposure of macitentan and its active metabolite does not significantly differ between patients with PoPH or other forms of PAH. These findings are of relevance as they suggest that portal hypertension, and the liver disease that may be its underlying cause, does not affect the PK of macitentan or its active metabolite in patients with PoPH. Please refer to page A266 for declarations of interest related to this abstract.
-
a phase 1 open label single dose study of the pharmacokinetics of buparlisib in subjects with mild to Severe Hepatic Impairment
2016Co-Authors: Denes Csonka, Katharine Hazell, Edward Waldron, Sebastien Lorenzo, Vincent Duval, Lucia Trandafir, Zhanna KobalavaAbstract:The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to Severe Hepatic Impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC∞] and Cmax) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 1.0–1.3 h). Buparlisib exposure (AUC∞) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or Severe (GMR 1.20; 90%CI 0.84, 1.72) Hepatic Impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the Severe group (0.21) than all other groups (0.17), subjects with Severe Hepatic Impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC∞ 1.52; 90%CI 1.09, 2.13; Cmax 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate Hepatic Impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with Severe Hepatic Impairment.
Richard Labotka - One of the best experts on this subject based on the ideXlab platform.
-
Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor
2019Co-Authors: Neeraj Gupta, Richard Labotka, R. Donald Harvey, Michael J. Hanley, Karthik VenkatakrishnanAbstract:Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal Impairment, or mild Hepatic Impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with Severe renal Impairment, end-stage renal disease requiring dialysis, or moderate-to-Severe Hepatic Impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for ixazomib. Drug–drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in ixazomib exposure, supporting the recommendation to avoid concomitant administration of ixazomib with strong CYP3A inducers. Exposure–response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit–risk profile for the approved dose and regimen of weekly ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.
-
pharmacokinetics of ixazomib an oral proteasome inhibitor in solid tumour patients with moderate or Severe Hepatic Impairment
2016Co-Authors: Neeraj Gupta, Karthik Venkatakrishnan, Michael J. Hanley, Raymond P. Perez, Robin E. Norris, John Nemunaitis, Huyuan Yang, Gerald Steven Falchook, Mark G Qian, Richard LabotkaAbstract:Aim The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or Severe Hepatic Impairment, to provide posology recommendations. Methods Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal Hepatic function, moderate Hepatic Impairment or Severe Hepatic Impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. Results Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and Severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/Severe Hepatic Impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal Hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. Conclusions In patients with moderate/Severe Hepatic Impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal Hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or Severe Hepatic Impairment.
-
A Phase 1 Study to Assess Pharmacokinetics (PK) and Safety of Ixazomib, an Oral Proteasome Inhibitor, in Patients with Moderate or Severe Hepatic Impairment
2015Co-Authors: Neeraj Gupta, Karthik Venkatakrishnan, Michael J. Hanley, Raymond P. Perez, Robin E. Norris, John Nemunaitis, Huyuan Yang, Gerald Steven Falchook, Richard LabotkaAbstract:Background The investigational oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in patients with multiple myeloma and amyloidosis. Metabolism is the major mechanism of ixazomib clearance; accordingly, Hepatic Impairment may increase ixazomib exposures. PK and safety data suggested no clinically relevant PK alterations in patients with mild Hepatic Impairment (Gupta et al BJCP 2015). This study (NCT01912222) was performed to characterize the PK of ixazomib in patients with moderate or Severe Hepatic Impairment, as defined by the NCI Organ Dysfunction Working Group, to develop dosing recommendations for these specific patient populations. Methods Eligible adults had advanced malignancies for which no further effective therapy was available. Twelve PK-evaluable patients were planned to be enrolled to each of the normal (N), moderate (M) or Severe (S) Hepatic Impairment groups. Patients received a single dose of ixazomib on day 1; those in the N, M, and S groups received ixazomib 4, 2.3, and 1.5 mg, respectively. Blood samples were collected at multiple time points for 15 days after dosing to characterize single dose PK (18 samples in total, 0.5-8 hr on day 1, days 2-8, days 11, 12, and 15). After completion of PK sampling, patients could continue on the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Geometric mean ratios and 90% CIs of unbound dose-normalized (DN) PK parameters in the Hepatic Impairment vs normal groups were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03. Results Forty-eight patients were enrolled (13, 15, and 20 patients to the N, M, and S groups, respectively); 32 were Caucasian, 10 African American, 2 Asian, and 4 other. Mean age was 56 years (range 24-83), mean weight 76 kg (range 43-127), and mean body surface area 1.9 m2 (range 1.4-2.5); 28 (58%) were male. The most common cancers were hepatocellular carcinoma (21%) and colorectal carcinoma, with or without liver metastases (10%). All patients in the S group had liver dysfunction due to primary or metastatic tumors. Forty-three patients had reportable PK parameters (Cmax or AUC) and were PK-evaluable (12 N, 13 M, 18 S). PK parameters are reported in the Table. Ixazomib was rapidly absorbed in all 3 Hepatic function groups examined, with a median Tmaxof 0.95-1.5 hours. Ixazomib was highly bound to plasma proteins with a similar mean fraction bound (~99%) in all 3 groups. Only 1 (2%) patient continued on study for more than 3 cycles (endometrial carcinoma, 10 cycles). Discontinuations were due to progression (75% of discontinuations), TEAEs or death related to progression. The most common TEAEs were nausea (38%), fatigue (31%), peripheral edema (31%), vomiting (27%), dyspnea (23%), decreased appetite (21%), and hyperbilirubinemia (21%). Most patients (77%) had a grade ≥3 TEAE, including 15% with a grade ≥3 study drug-related TEAE (dehydration [6%], fatigue [4%], anemia [2%], and fall [2%]); no patient had a study drug-related grade 4 TEAE. There were 14 on-study deaths, all of which were considered related to disease progression. Conclusions Unbound systemic exposures of ixazomib were 27% higher in patients with moderate or Severe Hepatic Impairment versus those in patients with normal Hepatic function. A reduced starting ixazomib dose of 3 mg is recommended for patients with moderate or Severe Hepatic Impairment. Disclosures Gupta:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Off Label Use: Investigational proteasome inhibitor ixazomib. Hanley:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Venkatakrishnan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Perez:Dompe: Research Funding; Eli Lilly: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Immunogen: Research Funding; Bristol Meyers Squibb: Research Funding; Agensys: Research Funding; PRA: Consultancy; Tetralogics: Research Funding. Norris:Nektar Pharmaceuticals: Consultancy. Yang:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Falchook:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.
-
a phase 1 study to assess pharmacokinetics pk and safety of ixazomib an oral proteasome inhibitor in patients with moderate or Severe Hepatic Impairment
2015Co-Authors: Neeraj Gupta, Karthik Venkatakrishnan, Michael J. Hanley, Raymond P. Perez, Robin E. Norris, John Nemunaitis, Huyuan Yang, Gerald Steven Falchook, Richard LabotkaAbstract:Abstract Background The investigational oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in patients with multiple myeloma and amyloidosis. Metabolism is the major mechanism of ixazomib clearance; accordingly, Hepatic Impairment may increase ixazomib exposures. PK and safety data suggested no clinically relevant PK alterations in patients with mild Hepatic Impairment (Gupta et al BJCP 2015). This study (NCT01912222) was performed to characterize the PK of ixazomib in patients with moderate or Severe Hepatic Impairment, as defined by the NCI Organ Dysfunction Working Group, to develop dosing recommendations for these specific patient populations. Methods Eligible adults had advanced malignancies for which no further effective therapy was available. Twelve PK-evaluable patients were planned to be enrolled to each of the normal (N), moderate (M) or Severe (S) Hepatic Impairment groups. Patients received a single dose of ixazomib on day 1; those in the N, M, and S groups received ixazomib 4, 2.3, and 1.5 mg, respectively. Blood samples were collected at multiple time points for 15 days after dosing to characterize single dose PK (18 samples in total, 0.5-8 hr on day 1, days 2-8, days 11, 12, and 15). After completion of PK sampling, patients could continue on the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Geometric mean ratios and 90% CIs of unbound dose-normalized (DN) PK parameters in the Hepatic Impairment vs normal groups were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03. Results Forty-eight patients were enrolled (13, 15, and 20 patients to the N, M, and S groups, respectively); 32 were Caucasian, 10 African American, 2 Asian, and 4 other. Mean age was 56 years (range 24-83), mean weight 76 kg (range 43-127), and mean body surface area 1.9 m2 (range 1.4-2.5); 28 (58%) were male. The most common cancers were hepatocellular carcinoma (21%) and colorectal carcinoma, with or without liver metastases (10%). All patients in the S group had liver dysfunction due to primary or metastatic tumors. Forty-three patients had reportable PK parameters (Cmax or AUC) and were PK-evaluable (12 N, 13 M, 18 S). PK parameters are reported in the Table. Ixazomib was rapidly absorbed in all 3 Hepatic function groups examined, with a median Tmaxof 0.95-1.5 hours. Ixazomib was highly bound to plasma proteins with a similar mean fraction bound (~99%) in all 3 groups. Only 1 (2%) patient continued on study for more than 3 cycles (endometrial carcinoma, 10 cycles). Discontinuations were due to progression (75% of discontinuations), TEAEs or death related to progression. The most common TEAEs were nausea (38%), fatigue (31%), peripheral edema (31%), vomiting (27%), dyspnea (23%), decreased appetite (21%), and hyperbilirubinemia (21%). Most patients (77%) had a grade ≥3 TEAE, including 15% with a grade ≥3 study drug-related TEAE (dehydration [6%], fatigue [4%], anemia [2%], and fall [2%]); no patient had a study drug-related grade 4 TEAE. There were 14 on-study deaths, all of which were considered related to disease progression. Conclusions Unbound systemic exposures of ixazomib were 27% higher in patients with moderate or Severe Hepatic Impairment versus those in patients with normal Hepatic function. A reduced starting ixazomib dose of 3 mg is recommended for patients with moderate or Severe Hepatic Impairment. Table . Hepatic function group PK parameters Geometric mean (%CV) Hepatic impaired vs Normal Least-squares geometric mean ratio (90% CI) Unbound DN Cmax (ng/mL/mg) Unbound DN AUC (ng.hr/mL/mg) Unbound DN Cmax Unbound DN AUC Normal 0.127 (47) 2.41 (50) N/A N/A Moderate 0.162 (80) 3.19 (61) 1.27 (0.74-2.18) 1.32 (0.70-2.50) Severe 0.154 (84) 2.96 (63) 1.21 (0.74-2.01) 1.23 (0.66-2.29) Moderate/Severe (combined) 0.158 (81) 3.07 (61) 1.24 (0.79-1.95) 1.27 (0.75-2.16) Cmax, maximum plasma concentration; CV, coefficient of variation; AUC, area under the plasma concentration-time curve Disclosures Gupta: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Off Label Use: Investigational proteasome inhibitor ixazomib. Hanley: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Venkatakrishnan: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Perez: Dompe: Research Funding; Eli Lilly: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Immunogen: Research Funding; Bristol Meyers Squibb: Research Funding; Agensys: Research Funding; PRA: Consultancy; Tetralogics: Research Funding. Norris: Nektar Pharmaceuticals: Consultancy. Yang: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Falchook: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Labotka: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.
