Plasma Pharmacokinetic Samples Research Articles

Enzalutamide in combination with docetaxel in men with prostate cancer (PC): Preliminary results from a phase I study.

63 Background: Enzalutamide (ENZA), a novel oral androgen receptor (AR) inhibitor, inhibits AR signaling via inhibition of androgen binding to the AR, AR nuclear translocation, and nuclear AR-DNA binding. ENZA demonstrated a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (Scher et al, NEJM 2012; 367:1187). A Phase III study in men with progressive chemotherapy-naïve disease (PREVAIL), is ongoing. Docetaxel (DOC) is the current standard first-line chemotherapy for mCRPC. CYP3A4, which plays a role in DOC clearance, is induced by ENZA. Patients (pts) eligible to receive DOC may benefit from continued AR inhibition with ENZA, provided the combination is well tolerated with no unacceptable drug-drug interactions. Methods: This study evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks, with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: As of 21 Sept. 2012, 22 pts have been enrolled, 3 did not complete both C1 and C2; PK and C1 and C2 safety data are currently available from 15 pts reported here. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone. Conclusions: This is the first evaluation of ENZA given in combination with DOC.In mCRPC pts ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.

A phase I study of S-222611 an oral reversible dual inhibitor of EGFR and HER2, in patients with solid tumors.

3100 Background: S-222611 is a novel oral, potent, reversible tyrosine kinase inhibitor with antiproliferative activity in human tumor cell lines expressing EGFR and/or HER2 in vitro and in mouse xenograft models. We conducted the first study in patients (pts) with solid tumors expressing EGFR or HER2. Methods: Daily oral doses of S-222611 were escalated in successive cohorts from 100 mg to a maximum 1600 mg, using a 3 + 3 design. Full plasma pharmacokinetic (PK) profiles were obtained in all pts for 7 days after a single dose on Day 1 and for 24 h following 21 days of once daily dosing (Cycle 1). Trough PK samples were drawn weekly during the first 3 weeks of daily dosing. A CT scan was performed at baseline and every 8 weeks post-dose to assess response (RECIST). Results: Of 23 treated pts (16 male) aged 24-77y, 19 completed Cycle 1. One dose-limiting toxicity (DLT) has been seen to date, a rash at 1200 mg, which resolved on interruption and dose reduction. Other adverse events related to drug, diarrhea, rash, and nausea, were mild (grade 1 or 2) but more frequent at higher doses. Tumor responses have been seen over a wide range of doses. One complete clinical response was observed at 1200 mg in a pt with HER2 positive breast carcinoma previously treated with lapatinib and trastuzumab. Two pts showed confirmed partial responses (one with EGFR positive renal cell carcinoma at 200 mg daily and one with EGFR and HER2 positive esophageal carcinoma at 400 mg daily); 2 pts showed unconfirmed partial responses and 3 pts (with vaginal, gastric and pancreatic adenoCa) showed stable disease for >6 months (mo); 2 pts have been treated for >12 mo. Plasma Cmax, AUC and steady state concentrations increased with dose up to 1200 mg, exceeding those eliciting maximal responses in mice. The plasma t½ is >24 h. Conclusions: S-222611 was generally tolerated well in doses up to 1200 mg, with only one DLT; rash, diarrhea and nausea have been readily manageable. PK data support once daily dosing to achieve highly effective concentrations. A substantial proportion of patients with HER2 or EGFR expressing tumors have shown partial responses or stable disease (>6 mo) and one patient has shown a complete clinical response.

Safety, Tolerability, and Pharmacokinetic Interactions of the Antituberculous Agent TMC207 (Bedaquiline) With Efavirenz in Healthy Volunteers

Drug-drug interactions complicate management of coinfection with HIV-1 and Mycobacterium tuberculosis. Bedaquiline (formerly TMC207), an investigational agent for the treatment of tuberculosis, is metabolized by cytochrome P450 (CYP) 3A which may be induced by the antiretroviral drug efavirenz. This was a phase 1 pharmacokinetic drug interaction trial. Each healthy volunteer received two 400 mg doses of bedaquiline, the first alone and the second with concomitant steady-state efavirenz. Plasma pharmacokinetic sampling for bedaquiline and its N-monodesmethyl metabolite was performed over 14 days after each bedaquiline dose. Steady-state efavirenz pharmacokinetics were also determined. Efavirenz metabolizer status was based on CYP2B6 composite 516/983 genotype. Thirty-three of 37 enrolled subjects completed the study. Geometric mean of ratios for bedaquiline with efavirenz versus bedaquiline alone were 0.82 [90% confidence interval (CI): 0.75 to 0.89] for the 14-day area under the concentration-time curve (AUC0-336 h) and 1.00 (90% CI: 0.88 to 1.13) for the maximum concentration (Cmax). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90% CI: 0.97 to 1.19) for AUC0-336 h and 1.89 (90% CI: 1.66 to 2.15) for C(max). There were no grade 3 or 4 clinical adverse events. One subject developed asymptomatic grade 3 serum transaminase elevation, prompting study drug discontinuation. Efavirenz concentrations stratified by CYP2B6 genotype were similar to historical data. Single-dose bedaquiline was well tolerated alone and with steady-state efavirenz. The effect of efavirenz on bedaquiline concentrations is unlikely to be clinically significant.

Pediatric Underdosing of Efavirenz

To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information. Open-label, multicenter, PK study. Forty-one HIV-infected Ugandan children (3-12 years) on efavirenz + lamivudine + abacavir were enrolled in a study of twice-daily to once-daily lamivudine + abacavir 36 weeks after antiretroviral therapy initiation in the ARROW trial. Once-daily efavirenz doses were 200, 250, 300, 350 mg for children weighing 10 to <15, 15 to <20, 20 to <25, 25 to <30 kg, respectively, using 200/50 mg capsules or halved 600 mg tablets in case of 300 and 350 mg doses. Intensive plasma PK sampling (t = 0, 1, 2, 4, 6, 8, 12 hours postobserved ingestion) was performed at steady state (PK1) and repeated 4 weeks later (PK2, including a further 24-hour sample). Forty-one and 39 children had evaluable efavirenz profiles at PK1 and PK2, respectively. Seventeen (41%) were boys. Five, 16, 17, 3 were in the 10 to <15, 15 to <20, 20 to <25, 25 to <30 kg weight bands. The geometric mean (%CV) the area under the concentration-time curve 0-24 hours postdose was 50.8 (90.8%) and 55.5 (82.7%) h·mg·L(-1) at PK1 and PK2, respectively. Six children at PK1 and 7 at PK2 had subtherapeutic C(8h) and/or C(12h) (<1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C(24h) <1.0 mg/L (median (interquartile range) [range] 1.1 (0.7-2.9) [0.3-18.4]). Ten children at PK1 and 11 at PK2 had C(8h) and/or C(12h) >4.0 mg/L; 12 of 41 (29%) at either visit. African children aged 3-12 years, on efavirenz dosed according to 2006 WHO/manufacturer's recommendations, had lower and highly variable efavirenz PK parameters compared with adult data from manufacturer's leaflet. There were no differences across weight bands, suggesting no major effect of using half tablets. Higher pediatric efavirenz doses, as per WHO 2010 recommendations, should be used and investigated further but may risk increasing the proportion of children with potentially toxic levels.

Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy Studies

AbstractAbstract 1813 Background:Investigational agent MLN9708, a modified dipeptidyl boronic acid, is a potent, reversible and specific inhibitor of the 20S proteasome being evaluated in phase 1 trials of patients with hematologic malignancies and solid tumors. Preliminary plasma pharmacokinetic (PK) data for MLN9708 administered intravenously (IV) and orally (PO) are reported. Both routes of administration are being studied using a twice-weekly schedule (Days 1, 4, 8, and 11 of a 21-day treatment cycle) and a weekly schedule (Days 1, 8, and 15 of a 28-day treatment cycle). MLN9708 completely hydrolyzes to the pharmacologically active boronic acid MLN2238 in aqueous solutions. Methods:Preliminary PK data from four ongoing phase 1 dose-escalation studies with MLN9708 have been analyzed: two studies investigating IV administration (C16001, n=27; C16002, n=7) and two studies of the oral formulation (C16003, n=9; C16004, n=5). In all studies blood samples were collected following the first and final dose of MLN9708 administered in Cycle 1, and trough samples were collected throughout Cycle 1 and at the start of Cycle 2. MLN9708 PK samples were analyzed for MLN2238 plasma and urine concentrations using LCMS/MS with LLOQ of 0.5 ng/mL for plasma samples. Data were analyzed using noncompartmental and compartmental modeling approaches. Plasma exposure parameters (Cmax, Tmax, AUC0-t, and t1/2) were estimated using WinNonlin software v5.2. Results:Following bolus IV administration of MLN9708, MLN2238 showed multi-exponential plasma disposition, characterized by a rapid initial disposition phase (t1/2 of <0.25 hr), an intermediate disposition phase, and a terminal disposition phase with t1/2 of >4 days. For twice-weekly dosing, the Day 1 and Day 11 extrapolated immediate post-IV bolus plasma concentration of MLN2238 (C0) was roughly dose proportional over the dose range (0.125 to 2.34 mg/m2). In contrast, both the Day 1 and Day 11 dosing interval plasma concentration-time AUCs showed dose proportional increases only over the higher dose range (1 to 2.34 mg/m2). There was approximately 3–4 fold accumulation of MLN2238 by Day 11 on the twice-weekly schedule. For weekly IV dosing of MLN9708, only lower dose levels have been studied to date (0.125 to 1.4 mg/m2) but the PK behavior appears to be similar to that for twice-weekly dosing, with the exception that MLN2238 accumulates to a lesser degree (approximately 2-fold). Following oral administration of MLN9708 capsules, there was rapid absorption of MLN2238 (Tmax approximately 1 hr). At the doses studied to date (0.24 to 1.2 mg/m2) for twice-weekly and weekly dosing of MLN9708, systemic exposures achieved with oral dosing were similar to those achieved with IV dosing on the same schedule, indicating that the oral bioavailability of MLN2238 is substantial. Conclusions:MLN9708 (measured as MLN2238) shows approximately dose linear PK over the higher range of doses tested (1 to 2.34 mg/m2). Current data suggest that oral MLN9708 is rapidly absorbed and is substantially bioavailable. Acknowledgment:We thank all study investigators, study managers, and study enrollees participating in studies C16001 (advanced nonhematologic malignancies), C16002 (lymphoma), C16003 (multiple myeloma), and C16004 (multiple myeloma) for providing PK data for analysis. Disclosures:Gupta:Millennium Pharmaceuticals, Inc.: Employment. Off Label Use: Investigational agent in clinical development for the treatment of solid tumors and hematologic malignancies. Liu:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment; Takeda, Inc.: Equity Ownership; Sanofi-Aventis: Equity Ownership; Pfizer: Equity Ownership. Kalebic:Millennium Pharmaceuticals, Inc.: Employment. Gomez-Navarro:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership.

Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer

9000 Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant BRAF kinase with preclinical activity. V600E BRAF is the most common kinase mutation in melanoma (60%), also found in colorectal carcinomas (10%), most anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas. Methods: Phase I, dose-escalation study designed to determine maximum tolerated dose (MTD), safety, pharmacokinetic (PK) / pharmacodynamic (PD), and efficacy (RECIST evaluation every 8 wks) of PLX4032 in sequential cohorts of 3 to 6 patients (pts). Plasma PK samples were collected on days 1, 8 and 15. Results: 54 pts have been enrolled: metastatic melanoma (n=49), thyroid (n=3), rectal (n=1), or ovarian carcinoma (n=1). 26 pts received a crystalline formulation (CF) continuously at doses from 100 mg BID to 1600 mg BID with associated exposures below target plasma levels. 28 pts received an optimized formulation with increased bioavailability, predicted to have 10-fold greater bioavailability, at doses from 160 mg BID to 1120 mg BID. AUC was dose-proportional and above target levels at 240 mg BID and higher. There was 1 DLT at 720 mg BID (G4 pancytopenia); treatment was restarted at 360 mg BID without myelosuppression. At 1120 mg BID, 3 of 5 pts had DLT (rash and fatigue). One pt had grade 3 increased ALT at 360 mg BID. 13 melanoma pts (77 %M1C) treated at doses of 240 mg BID or higher of the increased bioavailability formulation have a minimum follow-up of 8 weeks. 5 of the 7 BRAF V600E+ pts treated at ≥ 240 mg BID had tumor regression, up to 83%, with 1 confirmed partial response (PR) and 1 unconfirmed PR (too early); 2 of 4 pts with unknown V600E status had tumor regression, up to 50%, with 1 confirmed PR; 2 BRAF wild-type pts had progressive disease. All 7 pts with tumor regression remain progression-free, ranging from 4 to 14 months. 3 thyroid cancer pts with V600E mutations have tumor regression (range 9–16%) and are progression-free (4–7 months). Conclusions: Dose escalation of PLX4032 reached DLTs at 1120 mg BID. 720 mg BID is the current MTD, but 960 mg BID may be explored. PLX4032 exhibits antitumor activity in V600E BRAF mutant tumors. These observations confirm that V600E BRAF is a valid therapeutic target in human cancer. [Table: see text]

Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3–&lt;36 months

Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3-<36 months. Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration-time curve over 24 h (AUC(0-24)) and the maximum concentration (C(max)) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80-1.25 were considered bioequivalent. A total of 18 children (4, 6 and 8 in the 3-<12, 12-<24 and 24-<36 month age ranges, respectively) provided pharmacokinetic data for abacavir (17 for lamivudine). The GMR of AUC(0-24), once-daily versus twice-daily, was 1.07 (90% CI 0.92-1.23) for abacavir and 0.91 (90% CI 0.79-1.06) for lamivudine. C(max) almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73-2.42) and 1.78 (90% CI 1.52-2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNA<400 copies/ml, respectively. Bioequivalence was demonstrated on AUC(0-24) between twice-daily and once-daily abacavir; very similar AUC(0-24) values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3-<36 months.

Phase II trial of nolatrexed dihydrochloride [ThymitaqTM, AG 337] in patients with advanced hepatocellular carcinoma

To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma. Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced > or = grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method. Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1-12). The mean dose intensity was 700 mg/m(2)/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22-37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (C (max)) was 14.20 microg/mL (range 1.41 to 119 microg /mL) with no accumulation observed between cycles 1-6. This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.

Phase I trial of irofulven (MGI 114) in pediatric patients with solid tumors

We performed a Phase I trial of irofulven (MGI 114) to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the plasma pharmacokinetics of irofulven in children < or=21 years of age with refractory/recurrent malignancies. Thirty-five patients were entered into the study, of whom 34 were eligible. Patients received Irofulven daily x 5 days every 28 days over 10 min, following pre-treatment with ondansetron (0.45 mg/kg) and dexamethasone (12 mg/m(2)). The initial dose of irofulven was 8 mg/m(2) daily, with subsequent escalations to 10, 13, and 17 mg/m(2). Plasma pharmacokinetic samples were obtained in a subset patients. Thirty-two patients were assessable for toxicity, and 30 were assessable for response. In heavily pre-treated patients, dose-limiting thrombocytopenia was observed in two patients at the 8 mg/m(2)/day, and in one patient at the 6 mg/m(2)/day dose level. In less heavily pre-treated patients, proteinuria and elevated creatinine were dose limiting in two patients at the 17 mg/m(2)/day dose level. At 13 mg/m(2)/day, constipation, hyperkalemia with elevated creatinine, and thrombocytopenia was dose limiting in three patients. There were no complete or partial responses. One patient with poorly differentiated carcinoma had stable disease and received 11 courses of therapy. Patients demonstrated a lower systemic exposure and greater clearance than adults treated at similar dose levels. The MTD of irofulven administered daily x 5 every 28 days with concomitant ondansetron and dexamethasone is 6 mg/m(2)/day in heavily pre-treated patients and 10 mg/m(2)/day in less heavily pre-treated patients.

Phase I Clinical Trial of IPI-504, a Novel, Water-Soluble Hsp90 Inhibitor, in Patients with Relapsed/Refractory Multiple Myeloma (MM).

IPI-504 is a novel, water-soluble Heat Shock Protein 90 (Hsp90) inhibitor. It is the chemical reduction product of 17-AAG, a well-characterized Hsp90 inhibitor. 17-AAG is currently in clinical trials, but suffers from very poor aqueous solubility and must be administered to patients in either suboptimal DMSO formulations, or newer cremophor or emulsion formulations. IPI-504, however, exists as a hydrochloride salt which is soluble in water in excess of 100 mg/mL. It has previously been shown that IPI-504 inter-converts with 17-AAG and exists in a pH and enzyme-mediated dynamic redox equilibrium. When IPI-504 or 17-AAG is administered to mice, rats, or monkeys a dynamic equilibrium occurs in vivo in which both species are present in plasma as well as tissue. Thus, IPI-504 recapitulates all of the Hsp90 inhibitory properties and biological activity of 17-AAG without its formulation liabilities. In preclinical studies IPI-504 has demonstrated in vitro and in vivo anti-tumor effects in a variety of cancers including xenograft and orthotopic models of multiple myeloma. Therefore an open-label phase I dose-escalation trial of IPI-504 infused on days 1, 4, 8 and 11 of a 21 day cycle is being conducted in pts with relapsed/refractory MM. IPI-504 is infused in 250cc of normal saline over thirty minutes. Pts receive IPI-504 for one cycle of treatment. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and characterize the pharmacokinetic (PK) and pharmacodynamic (PD) marker effects of IPI-504. An accelerated titration design was utilized during the first three dose levels. Dose limiting toxicity (DLT) is defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 21 days of treatment. Results demonstrate that the in vivo dynamic equilibrium of IPI-504 and 17-AAG is detectable in human plasma PK samples and the water-based formulation is well-tolerated. Data on PK, dose proportionality, safety, tolerability, PD markers, and anti-tumor activity of IPI-504 will be reported. In conclusion, clinical evaluation of this agent is ongoing to define the safety, tolerability and potential activity of IPI-504 to treat pts with advanced MM. These results may help clarify the effects of Hsp90 inhibition using a water-soluble, ansamycin-based Hsp90 inhibitor without the confounding effects of DMSO-based formulations.

Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information‐dependent acquisition on a QTrap instrument

Bioanalytical support of plasma pharmacokinetic (PK) studies for drug discovery programs primarily involves the quantitative analysis of dosed compounds using liquid chromatography/atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) operated in selected reaction monitoring (SRM) mode. However, there is a growing need for information on the metabolism of new chemical entities (NCEs), in addition to the time-concentration profiles from these studies. In this paper, we present a novel approach to not only quantify parent drugs with SRM, but also simultaneously screen for metabolites using a hybrid triple quadrupole/linear ion trap (QqQ(LIT)) instrument. This was achieved by incorporating both the conventional SRM-only acquisition of parent compounds and the SRM-triggered information-dependent acquisition (IDA) of potential metabolites within the same scan cycle during the same LC/MS/MS run. Two test compounds were used to demonstrate the applicability of this approach. Plasma samples from PK studies were processed by simple protein precipitation and the supernatant was diluted with water before injection. The fast scanning capability of the linear ion trap allowed for the information-dependent acquisition of metabolite MS/MS spectra (<1 s/scan), in addition to the collection of adequate data points for SRM-only channels. The MS/MS spectra obtained from potential metabolites in post-dose samples correlated well with the spectra of the parent compounds studied, therefore providing additional confirmatory structure information without the need for repetitive analyses. Relative quantitative time-concentration profiles of identified metabolites were also obtained. Furthermore, this articulated SRM+SRM-IDA approach generated equivalent quantitative results for parent compounds to those obtained by conventional SRM-only analysis. This approach has been successfully used to support discovery PK screening programs.

Pediatric phase I trial and pharmacokinetic study of P-glycoprotein inhibitor, tariquidar, in combination with doxorubicin, vinorelbine or docetaxel

8541 Background: P-glycoprotein (Pgp), an ATP-dependent membrane transporter present in normal tissues, confers multidrug resistance in cancer cells. Tariquidar (TQ) blocks Pgp by inhibiting ATP binding and hydrolysis. Objectives: Assess toxicity, optimal dose, pharmacokinetics (PK) and pharmacodynamics of TQ in children with solid tumors and assess toxicity and PK of anticancer drugs (AD) in combination with TQ. Methods: TQ (1 [n=4], 1.5 [n=6], or 2 [n=5] mg/kg IV) was given alone on d 1 and with doxorubicin (DOXO, 50 mg/m2, n=10), docetaxel (75 mg/m2, n=4), or vinorelbine (20 mg/m2 d 3 & 10, n=1) on d 3. Plasma PK samples from d 1 & 3 were assayed for TQ by LC/MS/MS and DOXO by LC-fluorescent detection. Pgp function in vivo was assessed pre & post TQ using rhodamine uptake in CD56+ blood cells 24 h post TQ by flow cytometry (n=12) and 99mTc-sestamibi scintigraphy (n=6) immediately ater TQ. Results: 15 children (age 2–18, median 13) with sarcoma (n=8), adrenocortical carcinoma (n=3) or other (n=4) were enrolled. TQ was well tolerated at all dose levels. Delayed neutrophil recovery (n=2), grade 3 thrombocytopenia from docetaxel (n=1) and grade 3 mucositis (n=3) were prominent AD toxicities. AD toxicities may be more severe at the 2 mg/kg TQ dose. PK parameters for TQ alone are presented below. DOXO clearance (CL, n=8) was 400±150 mL/min/m2 given with TQ. Inhibition of rhodamine efflux in CD56+ cells was 54, 62, and 79% of maximum at the 1, 1.5 and 2 mg/kg doses of TQ. Sestamibi uptake increased by 1.7- to 4.1-fold (median, 2.6-fold) in liver and 1.2 to 1.4-fold in tumor (n=2) after TQ. Conclusions: 2 mg/kg TQ is well tolerated in children. TQ CL may be dose dependent, and at 2 mg/kg TQ CL is comparable to CL in adults. DOXO CL was comparable to published results. Pgp function in CD56+ blood cells is inhibited for ≥24 h. TQ also enhanced retention of sestamibi in liver and in some tumors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration QLT, Inc.; Xenova Group, plc QLT, Inc.; Xenova Group, plc Xenova Group, plc

Pediatric phase I trial and pharmacokinetic study of P-glycoprotein inhibitor, tariquidar, in combination with doxorubicin, vinorelbine or docetaxel

8541 Background: P-glycoprotein (Pgp), an ATP-dependent membrane transporter present in normal tissues, confers multidrug resistance in cancer cells. Tariquidar (TQ) blocks Pgp by inhibiting ATP binding and hydrolysis. Objectives: Assess toxicity, optimal dose, pharmacokinetics (PK) and pharmacodynamics of TQ in children with solid tumors and assess toxicity and PK of anticancer drugs (AD) in combination with TQ. Methods: TQ (1 [n=4], 1.5 [n=6], or 2 [n=5] mg/kg IV) was given alone on d 1 and with doxorubicin (DOXO, 50 mg/m2, n=10), docetaxel (75 mg/m2, n=4), or vinorelbine (20 mg/m2 d 3 & 10, n=1) on d 3. Plasma PK samples from d 1 & 3 were assayed for TQ by LC/MS/MS and DOXO by LC-fluorescent detection. Pgp function in vivo was assessed pre & post TQ using rhodamine uptake in CD56+ blood cells 24 h post TQ by flow cytometry (n=12) and 99mTc-sestamibi scintigraphy (n=6) immediately ater TQ. Results: 15 children (age 2–18, median 13) with sarcoma (n=8), adrenocortical carcinoma (n=3) or other (n=4) were enrolled. TQ was well tolerated at all dose levels. Delayed neutrophil recovery (n=2), grade 3 thrombocytopenia from docetaxel (n=1) and grade 3 mucositis (n=3) were prominent AD toxicities. AD toxicities may be more severe at the 2 mg/kg TQ dose. PK parameters for TQ alone are presented below. DOXO clearance (CL, n=8) was 400±150 mL/min/m2 given with TQ. Inhibition of rhodamine efflux in CD56+ cells was 54, 62, and 79% of maximum at the 1, 1.5 and 2 mg/kg doses of TQ. Sestamibi uptake increased by 1.7- to 4.1-fold (median, 2.6-fold) in liver and 1.2 to 1.4-fold in tumor (n=2) after TQ. Conclusions: 2 mg/kg TQ is well tolerated in children. TQ CL may be dose dependent, and at 2 mg/kg TQ CL is comparable to CL in adults. DOXO CL was comparable to published results. Pgp function in CD56+ blood cells is inhibited for ≥24 h. TQ also enhanced retention of sestamibi in liver and in some tumors. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration QLT, Inc.; Xenova Group, plc QLT, Inc.; Xenova Group, plc Xenova Group, plc

Pharmacokinetic interaction study evaluating the effect of BMS-275291 on the pharmacokinetics of paclitaxel and carboplatin in patients with advanced or metastatic non-small cell lung cancer (NSCLC)

7309 Background: BMS-275291 is an inhibitor of matrix metalloproteinases. A large randomized, placebo controlled Phase II/III clinical study has been conducted to examine whether adding BMS-275291 to carboplatin plus paclitaxel therapy would improve survival in advanced NSCLC. Objective: This study was conducted to examine the effect of BMS-275291 on the plasma pharmacokinetics (PK) of paclitaxel and carboplatin when administered together to patients with advanced NSCLC. Methods/Results: Treatment with intravenous infusion of paclitaxel (200 mg/m2) and carboplatin (AUC=6) was commenced on Day 1 and repeated q 21 days. BMS-275291 1200 mg was given orally daily starting on Day 2. PK sampling for paclitaxel and carboplatin were obtained on Day 1 and 22, and for BMS-275291 on Day 22. 18 patients (11 male, 7 female) with Stage IIIB or IV NSCLC were enrolled. The median age was 61.5 yrs. 2 patients had grade 4 hypersensitivity reactions to paclitaxel including 1 patient who had a cardiac arrest. Both patients recovered. Grade 3 or 4 neutropenia was seen in 7 and 3 patients respectively and grade 3 thrombocytopenia in 4 patients. 3 patients had grade 3 arthralgia or myalgia. 6 patients developed grade 1 or 2 rash. PK samples were obtained on both Day 1 and Day 22 from 11 patients for BMS-275291, 10 patients for paclitaxel, and 9 patients for carboplatin. The peak concentration (Cmax) and exposure (AUCT) of paclitaxel and carboplatin on Day 1 was not significantly different on Day 1 compared with Day 22 (see Table). The mean (±SD) steady state parameters for BMS-275291 on Day 22 were Cmax 6.2 (±3.4) μg/mL, AUCT 23.1 (±8.9) μg.h/mL and T1/2 5.3 (±1.9) h. Conclusion: Administration of BMS-275291 1200 mg qd does not significantly affect the pharmacokinetic profile of paclitaxel or carboplatin and the combination was generally well tolerable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

Changes in indinavir exposure over time: a case study in six HIV-1-infected children.

To study changes in indinavir exposure over time in HIV-1-infected children. Protease inhibitor (PI)-naive HIV-1-infected children were treated with indinavir, zidovudine and lamivudine. Steady-state plasma pharmacokinetic (PK) sampling was carried out as standard of care. The AUC(0-8) was targeted between 15 and 30 mg h/L. PK sampling was repeated after dosage adjustment until the AUC(0-8) reached target values. Patients were included when the time interval between PK samplings was > or =2 years and differences in dosage/m2 <10% between PK samplings 1 and 2. Corrections of dose for changes in body size were carried out. Six children were enrolled with a median age of 5.2 years (range 1.7-13.6 years). All had a viral load below 500 copies/mL. The geometric mean (GM) of the AUC(0-8) decreased from 25.3 mg h/L at the first PK-day to 19.1 mg h/L at the second PK-day [geometric mean ratio (GMR): 0.76 (95% C.I.: 0.48-1.20)]. The GM of Cmax decreased from 11.8 to 10.4 mg/L [GMR: 0.88 (95% C.I.: 0.59-1.32)]. The GM of Cmin decreased from 0.08 to 0.07 mg/L [GMR: 0.86 (95% C.I.: 0.62-1.18)]. All children had an AUC(0-8) above 15 mg h/L on the first PK-day; three had an AUC(0-8) below 15 mg h/L on the second PK-day. In two of these three children, the plasma viral load was >500 copies/mL. Changes in indinavir exposure were observed over time. In two patients, decreased indinavir exposure was associated with virological failure. Therapeutic drug monitoring should be carried out over time since this may prevent subtherapeutic dosing in children.