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Introduction: Since their initial discovery in 1989, grapefruit juice (GFJ)-drug interactions have received extensive interest from the scientific, medical, regulatory and lay communities. Although knowledge regarding the effects of GFJ on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited., Areas Covered: This article reviews the in vitro effects of GFJ and its constituents on the activity of CYP enzymes, organic anion-transporting polypeptides (OATPs), P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported AUC ratios for available GFJ-drug interaction studies are also provided. Relevant investigations were identified by searching the PubMed electronic database from 1989 to 2010., Expert Opinion: GFJ increases the bioavailability of some orally administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, GFJ can decrease the oral absorption of a few drugs that rely on OATPs in the gastrointestinal tract for their uptake. The number of drugs shown to interact with GFJ in vitro is far greater than the number of clinically relevant GFJ-drug interactions. For the majority of patients, complete avoidance of GFJ is unwarranted.

Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl

Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK‐positive metastatic non‐small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P‐gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug–drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A‐mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically‐based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration–time curve from time 0 to infinity [AUC∞] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC∞ ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC∞ by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC∞ by ~50%. Simulations of potential transporter‐mediated DDIs predicted that brigatinib may increase systemic exposures (AUC∞) of P‐gp substrates (e.g., digoxin and dabigatran) by 15%–43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP‐mediated efflux and OCT1‐mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information. [ABSTRACT FROM AUTHOR]

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE‐MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time‐to‐event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M‐protein] and progression‐free survival [PFS]) outcomes observed in TOURMALINE‐MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M‐protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M‐protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens. [ABSTRACT FROM AUTHOR]

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non‐small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum‐based chemotherapy. This population pharmacokinetic (PK) analysis describes the PK of mobocertinib and its active metabolites, AP32960, and AP32914, using data from two phase I studies in healthy volunteers (n = 110) and two phase I/II studies in patients with mNSCLC (n = 317), including the pivotal phase I/II study. The plasma PK of mobocertinib, AP32960, and AP32914 were well‐characterized by a joint semimechanistic model that included two compartments for mobocertinib with absorption via three transit compartments, two compartments for AP32960, and one compartment for AP32914. The observed time‐dependency in PK was described by an enzyme compartment with drug and metabolite concentration‐dependent stimulation of enzyme production, resulting in the enzyme increasing the apparent clearance of mobocertinib, AP32960, and AP32914. Effects of healthy volunteer status (vs. patients with mNSCLC) on apparent oral clearance of all three moieties and on apparent central volume of distribution for mobocertinib were included as structural covariates in the final model. No clinically meaningful differences in mobocertinib PK were observed based on age (18–86 years), race, sex, body weight (37.3–132 kg), mild‐to‐moderate renal impairment (estimated glomerular filtration rate 30–89 ml/min/1.73 m2 by modification of diet in renal disease equation), or mild‐to‐moderate hepatic impairment, suggesting that no dose adjustment is required based on these covariates in patients with mNSCLC. [ABSTRACT FROM AUTHOR]

The ALK in Lung Cancer Trial of brigAtinib in First Line (ALTA‐1L) compared brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor‐naive patients with ALK+ non‐small cell lung cancer (NSCLC). A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure‐efficacy and exposure‐safety analyses in ALTA‐1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time‐independent) and dynamic (time‐varying) exposure metrics and efficacy (progression‐free survival [PFS], objective response rate [ORR], and intracranial ORR [iORR]) and safety outcomes (selected grade ≥2 and grade ≥3 adverse events [AEs]) were evaluated using logistic regression and time‐to‐event analyses. There were no meaningful differences in brigatinib PK in the first‐line and second‐line settings, supporting use of the previous population PK model for the first‐line population. Exposure‐response analyses showed no significant effect of time‐varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher iORR (odds ratio: 1.13, 95% confidence interval: 1.01–1.28, p = 0.049). Across the observed median exposure (5th–95th percentile) at steady state for 180 mg once daily, the predicted probability of iORR was 0.83 (0.58–0.99). AEs significantly associated with higher exposure were elevated lipase (grade ≥3) and amylase (grade ≥2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit‐risk profile of first‐line brigatinib 180 mg once daily (7‐day lead‐in dose at 90 mg once daily) in patients with ALK+ NSCLC. [ABSTRACT FROM AUTHOR]

The BCR‐ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model‐based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration–time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed‐effects modeling. Ponatinib pharmacokinetics were described by a 2‐compartment model with first‐order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19‐85 years), race, body weight (40.7‐152.0 kg), total bilirubin (0.1‐3.16 mg/dL), alanine aminotransferase (6‐188 U/L), albumin (23.0‐52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady‐state average concentrations that are in the pharmacological range for BCR‐ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805 [ABSTRACT FROM AUTHOR]

Background and objectives: Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. Methods: Plasma concentration–time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). Results: Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. Conclusions: Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib. [ABSTRACT FROM AUTHOR]

In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3‐arm, open‐label, randomized, single‐dose, fixed‐sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single‐dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration‐time curve (AUC0–inf; geometric least‐squares mean [LSM] ratio [90%CI], 0.88 [0.83‐0.94]). Coadministration of itraconazole with brigatinib increased AUC0–inf (geometric LSM ratio [90%CI], 2.01 [1.84‐2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0–inf (geometric LSM ratio [90%CI], 0.20 [0.18‐0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors. [ABSTRACT FROM AUTHOR]

Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration-time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2-2.7 m2), sex, age (23-91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%. [ABSTRACT FROM AUTHOR]

Brigatinib, a next‐generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non–small‐cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90‐mg tablets) after a 10‐hour fast or after a high‐fat meal in a 2‐period, 2‐sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty‐four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK‐evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high‐fat meal) versus fasted conditions, with no effect on area under the concentration‐time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment‐emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high‐fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (−36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (−20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development. [ABSTRACT FROM AUTHOR]

This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.Trial ID: ClinicalTrials.gov # NCT01953783. [ABSTRACT FROM AUTHOR]

Abstract: At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty‐eight patients were enrolled across the 3 drug‐drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least‐squares mean area under the plasma concentration‐time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91‐1.31) and was 1.11 (0.86‐1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration‐time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least‐squares mean ratio of 0.26 [90%CI 0.18‐0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least‐squares mean ratio of 0.46 [90%CI 0.29‐0.73]) in the presence of rifampin. The clinical drug‐drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P‐glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib. [ABSTRACT FROM AUTHOR]

The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2-period, 2-sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma. The study was conducted in 2 parts. In cycle 1 (pharmacokinetic cycle), patients received a 4-mg dose of ixazomib as capsule A or capsule B on day 1, followed by a 4-mg dose of the alternate capsule formulation on day 15. Pharmacokinetic samples were collected over 216 hours postdose. After the pharmacokinetic cycle, patients could continue in the study and receive ixazomib (capsule B only) on days 1, 8, and 15 of each 28-day cycle. Twenty patients were enrolled; of these, 14 were included in the pharmacokinetic-evaluable population. Systemic exposures of ixazomib were similar after administration of capsule A or capsule B. The geometric least-squares mean ratios (capsule B versus capsule A) were 1.16 for Cmax (90% confidence interval [CI], 0.84-1.61) and 1.04 for AUC0-216 (90%CI, 0.91-1.18). The most frequently reported grade 3 drug-related adverse events were fatigue (15%) and nausea (10%); there were no grade 4 drug-related adverse events. These results support the combined analysis of data from studies that used either formulation of ixazomib during development. [ABSTRACT FROM AUTHOR]

This population analysis described the pharmacokinetics of bortezomib after twice-weekly, repeat-dose, intravenous administration in pediatric patients participating in 2 clinical trials: the phase 2 AALL07P1 (NCT00873093) trial in relapsed acute lymphoblastic leukemia and the phase 3 AAML1031 (NCT01371981) trial in de novo acute myelogenous leukemia. The sources of variability in the pharmacokinetic parameters were characterized and quantified to support dosing recommendations. Patients received intravenous bortezomib 1.3 mg/m2 twice-weekly, on days 1, 4, and 8 during specific blocks or cycles of both trials and on day 11 of block 1 of study AALL07P1, in combination with multiagent chemotherapy. Blood samples were obtained and the plasma was harvested on day 8 over 0-72 hours postdose to measure bortezomib concentrations by liquid chromatography-tandem mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling. Covariates were examined using forward addition ( P < .01)/backward elimination ( P < .001). Data were included from 104 patients (49%/51% acute lymphoblastic leukemia/acute myelogenous leukemia; 60%/40% aged 2-11 years/12-16 years). Bortezomib pharmacokinetics were described by a 3-compartment model with linear elimination. Body surface area adequately accounted for variability in clearance (exponent 0.97), supporting body surface area-based dosing. Stratified visual predictive check simulations verified that neither age group nor patient population represented sources of meaningful pharmacokinetic heterogeneity not accounted for by the final population pharmacokinetic model. Following administration of 1.3 mg/m2 intravenous bortezomib doses, body surface area-normalized clearance in pediatric patients was similar to that observed in adult patients, thereby indicating that this dose achieves similar systemic exposures in pediatric patients. [ABSTRACT FROM AUTHOR]

Ixazomib is the first oral proteasome inhibitor to be investigated in the clinic. This clinical study assessed whether the pharmacokinetics of ixazomib would be altered if administered after a high-calorie, high-fat meal. In a 2-period, 2-sequence, crossover study design, adult patients with advanced solid tumors or lymphoma received a 4-mg oral dose of ixazomib as immediate-release capsules on day 1 without food (fasted, administered following an overnight fast) or with food (fed, following consumption of a high-calorie, high-fat meal), followed by another dose on day 15 in the alternate food intake condition (fasted to fed or fed to fasted). Twenty-four patients were enrolled; of these, 15 were included in the pharmacokinetic-evaluable population. Administration of ixazomib after a high-fat meal reduced both the rate and extent of absorption of ixazomib. Under fed conditions, the median time to peak plasma concentration (Tmax) of ixazomib was delayed by approximately 3 hours compared with administration in the fasted state (1.02 hours vs 4.0 hours), and there was a 28% reduction in total systemic exposure (area under the curve, AUC) and a 69% reduction in peak plasma concentration (Cmax). Together, the results support the administration of ixazomib on an empty stomach, at least 1 hour before or at least 2 hours after food. These recommendations are reflected in the United States Prescribing Information for ixazomib ( identifier NCT01454076). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide-dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide-dexamethasone, in East Asian patients with relapsed/refractory MM. Methods: Adult patients with measurable disease who had received 1-3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1-21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability. Results: Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median Tmax of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49 %) patients had at least one drug-related grade =3 adverse event (AE); the most common were neutropenia (19 %), diarrhea (14 %), and thrombocytopenia (12 %). Twenty-eight of 43 (65 %) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg. Conclusions: The all-oral combination of ixazomib plus lenalidomide-dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions. [ABSTRACT FROM AUTHOR]

Aims Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. Methods A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam ( CYP3A probe), flurbiprofen ( CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Results Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μ m and 0.6 μ m, respectively). Conclusion The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. [ABSTRACT FROM AUTHOR]

Objective--To determine whether oral administration of metoclopramide or a commercially available powdered whole grapefruit (PWG) nutraceutical in combination with cyclosporine enhances systemic availability of cyclosporine in dogs. Sample--8 healthy mixed-breed dogs in part 1 and 6 of these 8 dogs in part 2. Procedures--Cyclosporine pharmacokinetics were determined over the course of 24 hours after oral administration of cyclosporine (5 mg/kg) alone, cyclosporine with metoclopramide (0.3 to 0.5 mg/kg), cyclosporine with 2 g of PWG, or cyclosporine combined with both metoclopramide and 2 g of PWG by use of a Latin square crossover study with a 14-day washout period between treatments. Sixty days later, 6 of the 8 dogs were given 10 g of PWG followed by cyclosporine, and pharmacokinetic parameters were compared with those previously obtained after administration of cyclosporine alone. Results--Although metoclopramide or coadministration of metoclopramide and 2 g of PWG had no effect on the pharmacokinetic parameters of cyclosporine, compared with results for cyclosporine alone, the higher (10-g) dose of PWG resulted in 29% faster mean time to maximal plasma cyclosporine concentration, 54% larger area under the curve, and 38% lower apparent oral clearance. Conclusions and Clinical Relevance--Adjustment of the cyclosporine dose may not be needed when metoclopramide is coadministered orally to prevent common adverse effects of cyclosporine. Powdered whole grapefruit has the potential to reduce the required orally administered dose of cyclosporine but only when PWG is used in an amount (at least 10 g) that is currently not cost-effective. [ABSTRACT FROM AUTHOR]