Apparent Pharmacokinetic Interaction Research Articles

Safety, pharmacokinetics, and efficacy of rifasutenizol, a novel dual-targeted antibacterial agent in healthy participants and patients in China with Helicobacter pylori infection: four randomised clinical trials

Due to the rapid development of antimicrobial resistance, the efficacy of most Helicobacter pylori eradication therapies have progressively decreased to an unacceptable level. Rifasutenizol (TNP-2198) is a new molecular entity with a synergistic dual mechanism of action currently under clinical development for the treatment of microaerophilic and anaerobic bacterial infections. We aimed to evaluate the safety, pharmacokinetics, and efficacy of rifasutenizol in healthy Chinese participants and patients with H pylori. We conducted four clinical trials of rifasutenizol capsules in healthy participants (aged 18-55 years) and patients with asymptomatic H pylori infection (aged 18-65 years) in a clinical trial centre in Jilin province, China. Trial 1 was a phase 1, double-blind, randomised, placebo-controlled, single ascending dose study, in which participants were enrolled into one of seven rifasutenizol dose groups (50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg) and were randomly assigned in a 4:1 ratio to study drug or placebo. Trial 2 was a phase 1, double-blind, randomised, placebo-controlled, multiple ascending dose study, in which patients were enrolled into one of three rifasutenizol dose groups (200 mg, 400 mg, or 600 mg) and were randomly assigned in a 3:1 ratio to study drug or placebo. Trial 3 was a phase 2a, open-label, randomised, multiple-dose, dose-finding study in which patients enrolled into one of four cohorts were randomly assigned in a 1:1:1:1 ratio to a rifasutenizol dual or triple regimen. Trial 4 was a phase 2b, open-label, randomised, multiple-dose, regimen exploration study, in which patients enrolled into one of five cohorts were randomly assigned in a 2:2:1:1:2 ratio to a rifasutenizol dual therapy, triple therapy, or a control cohort. Block randomisation (block size 4 or 8) was used in all four trials. The key primary endpoints for trials 1, 2, and 3 were the tolerability, safety, and pharmacokinetics of rifasutenizol. For trial 4, the primary endpoint was the eradication rate of H pylori. These four trials were registered at ClinicalTrials.gov (NCT06081699, NCT06081712, NCT06076681, and NCT06076694) and chinadrugtrials.org.cn (CTR20190734, CTR20192553, CTR20212050, and CTR20220625) and are completed. Between May 9, 2019, and Sept 14, 2022, 78 healthy participants (trial 1: n=10 per cohort in a 4:1 rifasutenizol:placebo ratio; and an additional eight for the food-effect cohort) and 168 patients with asymptomatic H pylori infection (trial 2: n=16 per cohort in a 3:1 rifasutenizol:placebo ratio; trial 3: n=10 per cohort; trial 4: n=10 or n=20 per cohort) were enrolled in the four clinical trials. Single doses of rifasutenizol (50-1000 mg) and multiple doses of rifasutenizol (200 mg to 600 mg, twice a day), either as monotherapy or co-administered with rabeprazole and amoxicillin, showed favourable safety and tolerability profiles. Most adverse events were mild, and no serious adverse events were reported. Rifasutenizol demonstrated a linear pharmacokinetic profile over the dose range of 50-800 mg, and there were no apparent pharmacokinetic interactions between rifasutenizol and the co-administrated drugs. Food intake slightly elevated the area under the plasma concentration-time curve (AUC) of rifasutenizol, and the geometric mean of AUC from time 0 to the last timepoint with a quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) in the fed state were 1·334 and 1·396 times of those in the fasted state, respectively. There was mild accumulation after continuous administration of rifasutenizol, and the Rac(AUC) of rifasutenizol 400 mg in the dual and triple regiments in trial 3 were 1·37 and 1·49, respectively. In trial 3, the eradication rates of H pylori with 200 mg, 400 mg, or 600 mg of rifasutenizol in combination with rabeprazole, twice a day for 14 days, were 0% (95% CI 0-31), 30% (7-65), and 40% (12-74), respectively, identifying rifasutenizol 400 mg as the effective dose. In trial 4, H pylori eradication rates with the triple regimen in cohort A (400 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) twice a day for 14 days was 95% (95% CI 74-100), and triple therapy (600 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) three times a day for 7 days was 100% (69-100). Rifasutenizol monotherapy and combination therapy was generally safe and well tolerated in healthy participants and patients with H pylori infection. A triple regimen of 400 mg rifasutenizol capsules, 20 mg rabeprazole sodium enteric-coated tablets, and 1 g amoxicillin capsules twice a day for 14 days showed promising efficacy as a new treatment regimen for H pylori infection. TenNor Therapeutics and National Natural Science Foundation of China. For the Chinese translation of the abstract see Supplementary Materials section.

Pharmacokinetic Interaction of Chiglitazar with CYP3A4 Inducer or Inhibitor: An Open-Label, Sequential Crossover, Self-Control, 3-Period Study in Healthy Chinese Volunteers.

Chiglitazar, a pan agonist of non-thiazolidinedione peroxisome proliferator-activated receptor, has the potential to regulate blood sugar, improve lipid metabolism, and reduce cardiovascular complications. This study aimed to examine the effect of cytochrome P450 (CYP) 3A4 inhibitors/inducers on the in vivo metabolism of chiglitazar and provide a reference for the clinical combination use of chiglitazar. A single-center, open-label, sequential crossover, and self-control study was carried out in 24 healthy subjects to determine the pharmacokinetics of chiglitazar dosed with and without CYP3A4 inhibitors and inducers. The findings showed that the CYP3A4 inhibitor itraconazole had no apparent pharmacokinetic drug interaction with chiglitazar, whereas rifampicin did. When combined with rifampicin after continuous dosing, chiglitazar exposure was not theoretically reduced but increased compared to a single dose of chiglitazar. The possible explanation may be the transporters of bile salt export pump, but this needs to be confirmed. The safety of chiglitazar in single or combination doses was well tolerated. The findings of this study provide a basis for clinical combinations of chiglitazar with CYP3A4 inhibitors or inducers.

No apparent pharmacokinetic interactions were found between henagliflozin: A novel sodium‐glucose co‐transporter 2 inhibitor and glimepiride in healthy Chinese male subjects

Henagliflozin is a novel selective sodium-glucose co-transporter 2 (SGLT2) inhibitor with similar inhibitory effect to ertugliflozin. Glimepiride is widely used to treat type 2 diabetes mellitus (T2DM) with few cardiovascular side effects. In the present study, we aimed at evaluating the pharmacokinetic (PK) interactions between henagliflozin and glimepiride. An open-label, single-centre, single-arm, 3-period, 3-treatment, self-control study was conducted in twelve healthy Chinese male subjects. During each study period, subjects received a single oral dose of glimepiride 2mg, multiple oral doses of henagliflozin 10mg or a combination of the two drugs. Serial blood samples were collected 24h post-dosing for PK analyses. Finger-tip blood glucose was also tested for safety evaluation. Co-administration of henagliflozin with glimepiride did not affect their plasma PK profiles. For henagliflozin, the 90% confidence intervals for the geometric mean ratio (GMR) for the maximum plasma concentrations at steady-state (Cmax ss ) and the area under the plasma concentration-time curve during a dosing interval at steady-state (AUCτ, ss ) of combination therapy to henagliflozin alone were 1.00 (0.93-1.08) and 1.00 (0.98-1.02), respectively. For glimepiride, the corresponding values of combination therapy to glimepiride alone were 1.00 (0.88-1.13) for maximum plasma concentrations (Cmax ), 0.91 (0.84-0.99) for the area under the plasma concentration-time curve from 0-24h (AUC0-24h ) and 0.91 (0.83-1.00) for the plasma concentration-time curve from 0h to infinite (AUC0-inf ), respectively. All values fell within the equivalence range of 0.8-1.25. All monotherapies and combination therapy led to no serious adverse events and were well tolerated. Multiple doses of henagliflozin did not exert a significant change on glimepiride PK profiles and a single dose of glimepiride had little effect on henagliflozin blood concentration. Thus, henagliflozin can be co-administered with glimepiride without dose adjustment of either drug.

Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice.

Approximately 20 million adults in the USA have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD. To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol. The effects of DOI were examined using ethanol-induced place conditioning (1.8g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3mg/kg) that produced the maximal response in the serotonin 2A (5-HT2A) receptor-dependent head-twitch assay. Interactions between DOI and ethanol (3g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation. DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT2A receptors, was selective for alcohol over water, and was selective for high alcohol-preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release. Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.

Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma

Sirolimus, an oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases, by vertical disruption of vascular epithelial growth factor receptor (VEGFR) signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients and also by directly inhibiting tumor cell proliferation. We conducted this phase 1 study to investigate the maximum tolerated dose (MTD) for this combination of sunitinib and sirolimus in humans. Sunitinib was given at 50mg daily×28 every 6weeks. The first cohort received sunitinib alone for cycle 1 (50mg daily for 2weeks followed by 2weeks off) and received sunitinib at standard dose 50mg daily for 4weeks followed by 2weeks off in combination with sirolimus 4mg weekly; this dose and schedule were further investigated in second cohort. The third cohort received decreased dose of sunitinib at 37.5mg daily for 4weeks followed by 2weeks off in combination with sirolimus at 4mg weekly. Sirolimus dose was escalated to 8mg weekly in fourth cohort. Eighteen patients with ECOG PS of 0 or 1 were enrolled, median age 57years (range 24-76), M:F ratio: 11:7. Median number of prior treatments is 2 (range 0-5); six patients had no prior systemic therapy. Half of patients from the first two cohorts required dose reduction or early discontinuation of treatment; therefore, sunitinib dose was decreased to 37.5mg daily in third and fourth cohort. In third and fourth cohort, one-third of patients required dose modification during cycle 1 or cycle 2. Multiple patients had significant toxicities including fatigue and hand-foot syndrome. One patient developed interstitial pneumonitis, and one patient died suddenly on day 8 due to progressive disease. There were six patients who tolerated four or more cycles. Among these six patients, two patients with renal cell carcinoma (RCC) achieved partial response; one subsequently underwent surgical resection of residual renal mass and lymph node dissection and achieved complete response afterward. One with metastatic melanoma also achieved complete response after metastatectomy. There was no apparent pharmacokinetic interaction between sunitinib and sirolimus. 4mg weekly sirolimus did not reduce the sunitinib-induced circulating VEGF production but stimulated more VEGF production through some unknown compensatory mechanism. Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.

Abstract PD5-2: Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer

Abstract Background: Taselisib (GDC-0032) is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant (MT) cancers. Taselisib is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PI3K alpha isoform (PIK3CA) MT breast cancer cell lines and enhanced antitumor activity when combined with letrozole. Clinical data with single-agent taselisib also showed increased tumor shrinkage in patients with PIK3CA MT breast cancer as compared to patients with PIK3CA wildtype (WT) breast cancer. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of taselisib doses ranging from 6-9 mg QD in combination with letrozole 2.5mg QD in a modified 3+3 design. A dose expansion cohort was conducted with taselisib 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment by FDG-PET, and anti-tumor activity by RECIST. Results: As of 31 January 2014, 28 patients were enrolled onto this study with the completion of dose escalation and the dose expansion cohort. No dose limiting toxicities (DLTs) were observed at either the 6 mg (n = 20) or 9 mg (n = 8) dose levels. Adverse events (AEs) assessed by the investigator as related to taselisib in ≥10% of patients (any grade) included diarrhea, nausea, stomatitis, fatigue, rash, decreased appetite, hyperglycemia, dysgeusia, mucosal inflammation, vomiting, muscle spasms, asthenia, dry mouth, dry skin, pruritus, and aspartate aminotransferase increased. Grade 3 and 4 adverse events assessed by the investigator as drug-related and occurring in greater than one patient included diarrhea (14%), hyperglycemia (7%), and mucosal inflammation (7%). No apparent PK interactions were observed between taselisib and letrozole. The median number of prior systemic therapies was six, and promising efficacy data has been observed in these heavily pretreated patients. Metabolic partial responses via FDG-PET (≥ 20% decrease in mean SUVmax) were observed in 11 out of 18 patients assessed (61%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg taselisib dose levels. For patients with measurable disease at baseline, the overall response rate of 38% was observed in patients with PIK3CA MT breast cancer and 9% in patients with PIK3CA WT breast cancer. Updated data on safety, PD, efficacy, and biomarker correlates will be presented. Conclusions: The combination of taselisib and letrozole is a well-tolerated regimen with promising preliminary efficacy in PIK3CA MT breast cancer patients. This preliminary Ph1b clinical data is consistent with taselisib preclinical and single-agent clinical data showing increased anti-tumor activity for taselisib in PIK3CA MT breast cancer as compared to PIK3CA WT breast cancer. Taselisib is being further investigated in the neoadjuvant setting in combination with letrozole in the LORELEI study in patients with untreated hormone receptor-positive breast cancer. Citation Format: Cristina Saura, Jasgit Sachdev, Manish R Patel, Andres Cervantes, Dejan Juric, Jeffrey R Infante, Donald Richards, Sandra Sanabria, Xuyang Lu, Joseph Ware, Timothy R Wilson, Hema Parmar, Jerry Y Hsu, Mafalda Oliveira, Eric P Winer, Daniel D Von Hoff, Jose Baselga, Ian E Krop. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-2.

Phase 1B Study of Oral Dual-Pi3K/Mtor Inhibitor Gdc-0980 in Combination with Carboplatin (Carbo)/Paclitaxel (Pac) ± Bevacizumab (Bev) and Cisplatin (Cis)/Pemetrexed (Pem) in Patients (Pts) with Advanced Solid Tumors and Nsclc

ABSTRACT Aim: The PI3K signaling pathway is altered in many tumor types, including NSCLC. GDC-0980 has single-agent activity as well as preclinical cytotoxic synergy with taxane and platinum agents and antiangiogenic synergy with anti-VEGF agents. Methods: This Phase 1b study evaluated the safety and tolerability of GDC-0980 in combination with platinum-based chemotherapy (CT) and Bev in pts with advanced solid tumors (AST) or first-line advanced NSCLC: Arm A – Carbo (AUC 6) + Pac (200 mg/m2); Arm B – Carbo/Pac + Bev (15 mg/kg); Arm C - Cis (75 mg/m2) + Pem (500 mg/m2). On a 21-day cycle, CT regimens were administered on Day 1, and GDC-0980 PO QD on Days 1-14. Pharmacokinetic (PK) analyses were performed. Archival tumor tissue and blood samples for pharmacogenetic and ctDNA analyses were collected. Results: Sixty-five pts (28 in Arm A [17 NSCLC]; 18 in Arm B [10 NSCLC]; 19 in Arm C [12 NSCLC]) were treated with GDC-0980 20 to 40 mg. For AST cohorts in Arms A and B, the MTD of GDC-0980 was 25 mg (DLTs were febrile neutropenia, rash, and fatigue). For NSCLC cohorts in Arms A and C, the maximum administered dose (MAD) was 30 mg GDC-0980. At this dose, Grade 3/4 adverse events (AEs) in >10% of all treated pts were neutropenia (59%), rash (24%), febrile neutropenia and anemia (12%) in Arm A and neutropenia (33%), anemia and fatigue (25%), hypertension, infection, and pneumonitis (17%) in Arm C. Other high-grade AEs of interest were less common: hyperglycemia in Arm A (6%) and Arm C (8%) and rash (8%) in Arm C. Among NSCLC pts treated with 30 mg GDC-0980, objective responses were observed in 9 of 14 (64%) pts in Arm A and 4 of 12 (33%) pts in Arm C. Other pts with follicular thyroid, ovarian, and urothelial cancers (Arm A) and angiosarcoma (Arm B) also had objective responses. There were no apparent PK interactions. Biomarker analysis is ongoing. Conclusions: The safety profile of GDC-0980 30 mg in combination with Carbo/Pac or Cis/Pem is consistent with that of the individual agents, and AEs were manageable and reversible. These GDC-0980 combinations have demonstrated preliminary activity in first-line NSCLC. Disclosure: O. Hamid: Consultant to Genenech; W. Lin: Employee of Genentech, Inc.; B. O'keeffe: Employee of Genentech, Inc.; M.R. Lackner: Employee of Genentech, Inc.; J. Spoerke: Employee of Genentech, Inc.; J. Ware: Employee of Genentech, Inc. All other authors have declared no conflicts of interest.

Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease.

A fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ≈1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure. Plasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM(®) software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model. For the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V 2/F).The population parameter estimates namely CL/F and V 2/F for umeclidinium were 218L/h and 1,160L and 40.9L/h and 268L for vilanterol. For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10% increase in bodyweight will result in a 2% increase in CL/F for umeclidinium and vilanterol and 6% increase in umeclidinium V 2/F. A 10% increase in age will provide a 7 and 4% decrease in umeclidinium and vilanterol CL/F, respectively. A 10% decrease in CLCR will result in a 3% decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination. There were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co-administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary.

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET. This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies. Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years. Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors.

Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer

Abstract Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST. Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented. Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.

Phase Ib study of chidamide (CS055), a new subtype-selective oral histone deacetylase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.

e19075 Background: Chidamide (CS055) is a new benzamide type of histone deacetylase (HDAC) inhibitor with subtype selective activity against HDAC1, 2, 3 and 10. Synergistic effect of chidamide combined with paclitaxel and carboplatin (PC) have been demonstrated in various in vitro studies. Chidamide has shown well-tolerated and favorable PK profiles in patients (pts) with advanced solid tumors and lymphomas.This phase Ib study was designed to assess the safety and pharmacokinetics of chidamide plus PC in pts with advanced non-small cell lung cancer (NSCLC). Methods: Chemonaive pts with stage IIIb or IV NSCLC were treated with the escalating doses of chidamide (20, 25, and 30mg) plus PC. Chidamide was oral administered twice per week. Paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg·min/mL) were given both on day 1 every 3 weeks. Pts with response or stable disease after four cycles maintained single chidamide therapy until disease progression or unacceptable toxicity. Results: No DLT was observed in the 20 mg (n=3) and 25 mg (n=3) cohorts. 2 DLTs occurred in the 30 mg cohort (n=4), where 1 pt experienced grade 4 thrombocytopenia at the end of the first cycle, and the other developed grade 3 neutropenia and grade 2 thrombocytopenia resulting in the delay of the 2nd treatment cycle for > 14 days. Therefore, chidamide in 25 mg was determined to be the MTD with this combination regimen. ≥ Grade 3 toxicities were thrombocytopenia (n=3) and neutropenia (n=1). 1 pt experienced grade 1 prolonged QTc. Co-administration had no significant effect on clearance of either chidamide or paclitaxel. 1 pt in the 20 mg cohort had confirmed partial response. Of 5 pts with brain metastases, 2 of them had complete disappearance of brain tumors after 4-cycle treatment. Conclusions: Chidamide plus PC was safe and well tolerated, with no apparent chidamide-paclitaxel pharmacokinetic interaction. Preliminary efficacy results suggest that chidamide combined with PC could provide benefit to NSCLC pts, with a potential interest of further observation of brain metastasis control in NSCLC with this regimen. Clinical trial information: ChiCTR-ONC-12002283.

Herb–drug pharmacokinetic interaction of artificial calculus bovis with diclofenac sodium and chlorpheniramine maleate in rats

To investigate the herb-drug pharmacokinetic interaction of artificial calculus bovis (ACB) with diclofenac sodium (DS) and chlorpheniramine maleate (CPM) in rats. A sensitive high-performance liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the simultaneous determination of DS and CPM in rat plasma. The proposed method was successfully applied to compare the herb-drug pharmacokinetic interaction of ACB with DS and CPM in rats following intragastric administration. The proposed method had good linearity and no endogenous material interfered with the analytes and internal standard peaks. The lower limit of quantification of DS and CPM was 1 and 0.1 ng/ml, respectively. There was no apparent pharmacokinetic interaction between DS and CPM. Co-administration of ACB with DS noticeably increased the area under the concentration-time curve (AUC0-∞ ) and peak plasma concentration (Cmax ) of DS, while the parameters time of peak concentration (Tmax ), clearance (ClZ/F ) and apparent volume of distribution (VZ/F ) of DS significantly decreased. Meanwhile, co-administration of ACB with CPM noticeably increased the Tmax , ClZ/F and VZ/F of CPM. A marked decline in AUC0-∞ and Cmax of CPM occurred in the presence of ACB. This study indicated that co-administration of ACB with DS and CPM can result in an apparent herb-drug pharmacokinetic interaction in rats.

Single- and Multiple-Dose Study To Determine the Safety, Tolerability, and Pharmacokinetics of Ceftaroline Fosamil in Combination with Avibactam in Healthy Subjects

This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-β-lactam β-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option.

Phase I Study of Vorinostat in Combination with Temozolomide in Patients with High-Grade Gliomas: North American Brain Tumor Consortium Study 04-03

A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles. In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.

A phase I safety and pharmacokinetic (PK) study of navitoclax (N) in combination with docetaxel (D) in patients (pts) with solid tumors.

2518 Background: N (ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates D activity across a variety of solid tumor types. This phase I study was performed to determine the maximum tolerated dose (MTD) and to assess the safety and PK profile of N plus D. Methods: Pts with advanced solid tumors, adequate organ function and ECOG performance status ≤1 were eligible. N at 150 and 200 mg was given PO, QD days (d) 1-3 or d1-5 q21 followed by D 75 mg/ m2 IV on d 1 q21. To compare the PK of either agent alone, N was administered on days 3-5 or 3-7 only in course 2. PK samples were collected for N and D in cycles 1 and 2. Adverse events (AE) were graded by NCI CTCAE V3.0. Results: 15 pts (M/F: 8/7; median age 54 yrs (range 30-71) were treated at 3 dose levels of N: 150 mg and 200mg d1-5 and 200 mg d1-3. DLTs were febrile neutropenia and grade (gr) 4 thrombocytopenia at N 200 mg d1-5 and febrile neutropenia at 200 mg d 1-3. The MTD is set at 150 mg N d1-5 with D 75 mg2 on d1 and at this dose 12 additional pts are currently being enrolled. Other gr 3/4 AEs were neutropenia (43%), fatigue (21%) and thrombocytopenia (14%); frequently occurring grade 1/2 AEs were fatigue (57%), nausea (50%), vomiting (43%), anorexia (36%), constipation (29%), diarrhea (29%), and thrombocytopenia (21%). One pt with NSCLC had a confirmed partial response (PR), one pt with breast cancer had an unconfirmed PR. Five pts showed stable disease; duration of this ranged from 5-18 weeks; 3/5 pts had SD up to 12 weeks, 1/5 pts had SD up to 14 weeks, and 1/5 pts had SD for 18 weeks. Based on limited PK data, there was no apparent PK interaction between N and D (Table). Conclusions: Navitoclax 150 mg for d1-5 can be safely administrated with D 75 mg/m2. This combination is tolerable with no apparent PK interactions. Antitumor activity was observed in 7 pts (2 PR, 5 SD). Cmax/dose (ng/mL/mg)* AUC24/dose (ng*hr/mL/mg)* Navitoclax (150-200 mg, N=7) Navitoclax alone 20.9 ± 10.4 293 ± 174 Navitoclax with D 14.7 ± 11.4 222 ± 166 D (75 mg/m2, N=3) Cmax ( µ g/mL)* AUCinf ( µ g*hr/mL)* D alone 2.6 ± 1.2 2.9 ± 1.2 D with navitoclax 2.3 ± 0.7 2.4 ± 0.7 * Mean +/− SD

Abstract 5473: The contribution of P-glycoprotein to clinical pharmacokinetic interactions between lenalidomide and temsirolimus

Abstract Purpose: To evaluate the source of an apparent clinical pharmacokinetic interaction between lenalidomide (an Immunomodulatory Drug, IMiD) and temsirolimus (mTOR inhibitor). Background: The combination of lenalidomide with temsirolimus demonstrated a synergistic effect in in vitro models of Multiple Myeloma (MM), thus providing rationale for this combination in patients with relapsed MM. However pharmacokinetic interactions between these two agents have not been reported. In the current study, clinical pharmacokinetic interactions of lenalidomide with temsirolimus and the underlying mechanisms were investigated. Methods: A phase I clinical trial was completed for patients with relapsed multiple myeloma with oral lenalidomide (15-25 mg) days 1-21 of a 28 day cycle and weekly × 4 intravenous temsirolimus (15-20 mg). Pharmacokinetic data for both agents were obtained and potential drug-drug interactions were further evaluated using in vitro transport and uptake studies. An apparent clinical interaction was observed between lenalidomide and temsirolimus as demonstrated by statistically significant changes in clearance, maximum concentrations (Cmax), and area under the concentration-time curves (AUCs) for constant doses of lenalidomide with increased doses of temsirolimus. Similar and significant changes for temsirolimus pharmacokinetics at a fixed dose were also observed when lenalidomide doses were increased. In vitro studies indicated a higher basolateral-to-apical (BL-to-AP) flux compared to AP-to-BL flux for lenalidomide in MDCKII monolayers, suggesting an apically directed active transport of lenalidomide. Further evaluation of intracellular lenalidomide uptake showed an approximately 2-fold higher accumulation of lenalidomide in HL-60 than in P-glycoprotein (P-gp, ABCB1, MDR-1)-overexpressing HL-60/VCR cells (38.4 ± 13.2 vs. 19.2 ± 9.6 pmol/mg protein, respectively, P=0.005). Co-incubation with temsirolimus, a known P-gp substrate and inhibitor, resulted in increased lenalidomide accumulation (37.2 ± 6.0 vs. 19.2 ± 9.6 pmol/mg protein, respectively, P=0.002) in HL-60/VCR cells, which was equivalent to that in HL-60 cells. Clinical significance of this pharmacokinetic interaction in terms of either toxicity or response has also been evaluated. Conclusions: These results suggest that lenalidomide is a P-gp substrate, explaining the pharmacokinetic interaction between lenalidomide and temsirolimus. Quantifying the interaction of lenalidomide with other P-gp substrates, e.g. dexamethasone, is warranted to optimize dose administration of IMiD-based therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2011-5473

Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors

NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. NGR-hTNF was escalated using a doubling-dose scheme (0.2-0.4-0.8-1.6 μg/m(2)) in combination with fixed-dose of cisplatin (80 mg/m(2)), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m(2) (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m(2). This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m(2) (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m(2). At the dose level of 0.8 μg/m(2), expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. The combination of NGR-hTNF 0.8 μg/m(2) with cisplatin 80 mg/m(2) showed favorable toxicity profile and promising antitumor activity.

Combination mTOR and IGF-1R Inhibition: Phase I Trial of Everolimus and Figitumumab in Patients with Advanced Sarcomas and Other Solid Tumors

Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG(2) anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated. Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1. No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab. Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation.

A Phase I Study of Vandetanib in Combination with Vinorelbine/Cisplatin or Gemcitabine/Cisplatin as First-Line Treatment for Advanced Non-small Cell Lung Cancer

Vandetanib is a once-daily oral agent that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET (REarranged during Transfection) signaling. This Phase I study investigated the safety, tolerability, and pharmacokinetics of vandetanib when administered with either gemcitabine plus cisplatin (GC) or vinorelbine plus cisplatin (VC) in patients with previously untreated locally advanced or metastatic non-small cell lung cancer. Seventeen patients received vandetanib 100 mg/d plus VC (n = 9) or GC (n = 8). Three dose-limiting toxicities were reported in each treatment group: vandetanib + VC (pulmonary artery thrombosis and asymptomatic QTc prolongation [n = 2]); vandetanib + GC (peripheral ischemia [due to arterial occlusion], pulmonary embolism, and limb venous thrombosis). The protocol definition of a tolerable dose was not met, and no patients were recruited to receive vandetanib 300 mg plus VC or GC. There was no apparent pharmacokinetic interaction between vandetanib and vinorelbine or gemcitabine, but there was an approximate 30% increase in the exposure to cisplatin, which may be due to accumulation of total platinum and/or an interaction with vandetanib. In this study, in patients with previously untreated advanced non-small cell lung cancer, vandetanib 100 mg/d in combination with either VC or GC was not tolerated.

Optimal Everolimus Concentration Is Associated With Risk Reduction for Acute Rejection in De Novo Renal Transplant Recipients

Everolimus (Evl) plus tacrolimus (Tac) in de novo renal transplantation is effective and safe. Whether the concentration of Evl affects efficacy and safety in a Tac-based regimen has not been previously reported. To evaluate whether the concentration of Evl affects biopsy-proven acute rejection (BPAR), renal function, adverse events (AEs); and to assess for pharmacokinetic (PK) interactions. Data were from a prospective, multicenter, open-label, randomized, exploratory 6-month study of 92 renal transplant patients treated de novo with concentration-controlled Evl (target trough levels > or =3 ng/mL) plus low-dose Tac or Evl plus standard-dose Tac; both groups received basiliximab and corticosteroids. Data were pooled across study arms to examine BPAR rates in patients with Evl trough levels less than 3 (n=26), 3 to 8 (n=62), or more than 8 ng/mL (n=4). Groups were stratified by both Evl and Tac trough levels to evaluate glomerular filtration rate and AEs. Evl and Tac PK interactions were evaluated in a subset of 14 patients. Evl trough level of more than or equal to 3 ng/mL was associated with significantly lower rates of BPAR as compared with a trough level of less than 3 ng/mL. Glomerular filtration rate was similar at 6 months for both the low and standard Tac groups. No apparent PK interactions were observed between Evl and Tac. AEs were infrequent and did not seem to be associated with the Evl or Tac level. Evl trough levels > or =3 ng/mL plus Tac are associated with low rates of BPAR without adversely affecting renal function. No evident PK interaction exists between Evl and Tac.