A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors.

BACKGROUND: Resistance to chemotherapy can partly be explained by the activity of membrane bound P-glycoprotein. Competitive inhibition of P-glycoprotein, by multidrug resistance (MDR) converters, may overcome this MDR. Previously studied MDR converters either have serious intrinsic side effects or considerably influence the pharmacokinetics of cytotoxic agents at concentrations theoretically required to convert MDR. GF120918 is a third-generation MDR converter with high affinity for P-glycoprotein and can be given orally. We performed a phase 1 study with escalating doses of GF120918 in combination with doxorubicin. PATIENTS AND METHODS: The study group comprised 46 patients with advanced solid tumors. Doxorubicin was administered on day 1 (cycle 1), GF120918 on days 22-24 (cycle 2), and on days 29-33 with doxorubicin administered on day 31 (cycle 3). Pharmacokinetics of both GF120918 and doxorubicin were studied. The starting daily dose of GF120918 was 50 mg and was to be increased in subsequent cohorts until a steady state plasma level of 100 ng/ml was reached. The starting dose of doxorubicin was 50 mg/m2 and was to be increased after reaching the target dose level of GF120918. RESULTS: In 37 of the 46 patients, full pharmacokinetic data from the three scheduled cycles were obtained. Pharmacokinetics of GF120918 showed a less than linear increase in Cmax with increasing doses, with considerable interpatient variation. The target steady-state plasma level for GF120918 was exceeded in 12 out of 19 patients who received 400 mg GF120918 alone twice daily and in 12 of 17 patients who received 400 mg GF120918 twice daily in combination with doxorubicin. GF120918 pharmacokinetics were not influenced by coadministration of doxorubicin. The doxorubicin AUC was only marginally influenced by GF120918 and only at the highest dose levels. In these patients there was a significant increase in the AUC of doxorubicinol in cycle 3 as compared to cycle 1. Hematologic toxicity mainly consisted of neutropenia and was more severe in cycle 3 than in cycle 1 (13 vs 5 patients with grade 4 neutropenia, P=0.003). Neutropenic fever was the dose-limiting toxicity at a doxorubicin dose of 75 mg/m2 with 400 mg GF120918 twice daily. The toxicity of GF120918 was limited to somnolence in eight patients and occasional gastrointestinal complaints. CONCLUSION: GF120918 is an MDR converter with only minimal side effects at a dose level yielding concentrations able to convert the action of P-glycoprotein in vitro. A doxorubicin dose of 60 mg/m2 on day 3 in combination with 400 mg GF120918 twice daily on days 1-5 is an acceptable regimen for further clinical trials.

Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918.

PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate-binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m(2) oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m(2) intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 +/- 9.6 microg.h/L without GF120918 to 78.7 +/- 20.6 microg.h/L when GF120918 was coadministered (P =.008). The mean maximum plasma concentration of total topotecan increased from 4.1 +/- 1.5 microg/L without GF120918 to 11.5 +/- 2.4 microg/L with GF120918 (P =.008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P =.008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.

Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients.

Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m(2)in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m(2)as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration-time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 +/- 1.67 microM x h. In our previously performed study of 120 mg/m(2)oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 +/- 2.29 microM x h. After i.v. administration of paclitaxel the mean AUC was 15.92( )+/- 2.46 microM x h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel.

Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein.

Previous clinical investigations with doxorubicin indicated that modulators of P-glycoprotein dramatically decrease the systemic clearance of the drug, which complicates the interpretation of toxicity and response data. In the present study, we examined the pharmacokinetics of doxorubicin and GF120918, a novel potent P-glycoprotein inhibitor, in cancer patients in a search for more selective modulation of multidrug resistance (MDR). Seven cohorts (46 patients) received sequential treatments with doxorubicin alone by a 5 min i.v. bolus (50-75 mg/m2), oral GF120918 alone (50 mg q.d.-400 mg b.i.d.), and the combination of doxorubicin and GF120918. Serial blood and urine samples were taken during both treatment courses and analyzed for doxorubicin and its metabolite doxorubicinol by a liquid chromatographic assay. The pharmacokinetic characteristics of doxorubicin in the presence or absence of GF120918 indicate a very minor overall effect of the modulator, except at the highest combined dose level (i.e. 75 mg/m2 plus 400 mg b.i.d.). A limited number of patients experienced significantly increased exposure to doxorubicinol upon combined treatment, which was associated with concomitantly higher plasma levels of GF120918. Sigmoidal maximum-effect models revealed significant correlations (p<0.02) between the area under the curve of doxorubicinol and the percent decrease in neutrophils and platelets. Sigmoidicity factors in the fitted Hill equation were similar between both treatment courses, suggesting no pharmacodynamic potentiation of doxorubicinol myelotoxicity by GF120918. Our data indicate that GF120918 at the tested doses of combination treatment achieves plasma concentrations that reverse MDR in experimental models and it lacks the significant kinetic interaction with doxorubicin observed previously with other modulators. Hence, it may be possible in future trials to assess the contribution of a potent inhibitor of P-glycoprotein activity to the toxicity and activity of doxorubicin with the knowledge that profound plasma pharmacokinetic interactions are unlikely.

Pharmacokinetics of RheothRx injection in healthy male volunteers.

The objectives of this study were to evaluate the safety and tolerability of RheothRx (poloxamer 188) injection administered as an intravenous (i.v.) infusion to healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. Thirty-six healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation trial for RheothRx injection. The volunteers were randomized to three treatment groups (12 per treatment group, with eight receiving active therapy and four receiving placebo). In each treatment group, volunteers received RheothRx injection or placebo as an i.v. infusion on two occasions at least 3 weeks apart to make a total of six doses being studied (10, 30, and 45 mg/kg/h for 72 h, 60 mg/kg/h for 43.3 to 72 h, 60 and 90 mg/kg/h for 24 h). Serial plasma samples were collected during and up to 36 h after the end of the infusions; urine was collected over intervals from the start of the infusion until 36 h after the infusions were terminated. Plasma and urine samples were assayed for poloxamer 188 by gel-permeation chromatography. Pharmacokinetic parameter values were calculated by noncompartmental and compartmental methods. Poloxamer 188 was eliminated primarily by renal excretion. Estimates of clearance, elimination rate constant, and apparent volume of distribution at steady state values were independent of infusion rate. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

Effects of probenecid on the pharmacokinetics and pharmacodynamics of adinazolam in humans.

The effects of probenecid (2 gm) on the pharmacokinetics, pharmacodynamics, and uricosuric effects of adinazolam and N-desmethyladinazolam were assessed after single dose administration of adinazolam mesylate sustained-release tablets (60 mg) in a randomized, four-way crossover, double-blind study involving 16 healthy male volunteers. Probenecid decreased adinazolam oral clearance, renal N-desmethyladinazolam clearance, and the amount of N-desmethyladinazolam excreted in the urine. Probenecid increased the N-desmethyladinazolam/adinazolam AUC ratio, adinazolam maximum concentration (Cmax), N-desmethyladinazolam Cmax, and N-desmethyladinazolam time to reach Cmax. Uric acid renal clearance was increased significantly by adinazolam or probenecid administration compared with placebo; however, coadministration of adinazolam plus probenecid had no additive effect on uric acid clearance. Psychomotor performance was decreased in the adinazolam plus probenecid treatment compared with the adinazolam treatment. Probenecid potentiated the psychomotor effects of adinazolam after coadministration of the compounds, predominantly because of alterations in N-desmethyladinazolam pharmacokinetics. Therefore the adinazolam dose may need to be reduced when coadministered with probenecid.

Dose proportionality of transdermal nitroglycerin.

The FDA Cooperative Efficacy Study of transdermal nitroglycerin utilized a combination of marketed products over a wide dose range. Unfortunately, plasma nitroglycerin concentrations were not determined. The current study was conducted to assess plasma nitrate concentrations after transdermal doses of 15, 30, 60, and 105 mg/24 hr employing the FDA Cooperative Study design. Plasma concentrations of nitroglycerin, 1,3-glyceryl dinitrate, and 1,2-glyceryl dinitrate were determined during the 24 hr of application and for 1 hr after transdermal system removal. Dose proportionality was assessed after normalizing the data by theoretical dose. For nitroglycerin, dose-normalized AUC(0-infinity) and Cmax were higher for the 105 mg/24 hr dose than for the other doses. For the metabolites, 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate, there were no differences in dose-normalized AUC(0-infinity) and dose-normalized Cmax between the dose levels. No differences were seen in Tmax between the dose levels for all three species. Based on the dinitrate metabolites, dose proportionality was seen over the 15 to 105 mg/24 hr dose range. Nitroglycerin, however, was found to be linear only between 15 and 60 mg/24 hr.

Glutathione catalysis of interconversion of acitretin and its 13-cis isomer isoacitretin.

The ability of glutathione to catalyze the cis-trans isomerization of acitretin and isoacitretin was explored. Glutathione catalyzed the isomerization reaction in both directions; the reaction rate varied with glutathione concentration, atmospheric exposure condition, and identity of starting isomer. The ability of this widely distributed molecule to catalyze this interconversion nonenzymatically may contribute to the presence of both isomers in vivo after administration of either isomer.

Alpha 1-acid glycoprotein high-performance liquid chromatography column (EnantioPAC) as a screening tool for protein binding.

An attempt was made to correlate retention behavior on a high-performance liquid chromatographic (HPLC) system employing an immobilized alpha 1-acid glycoprotein (AAG) column with AAG binding behavior for various compounds. Protein binding was assessed by propranolol displacement studies in an equilibrium dialysis system using isolated AAG. HPLC retention behavior poorly correlated with propranolol displacement from AAG. This system is not suitable for use as a screening tool for AAG affinity.

Food increases the bioavailability of acitretin.

Eighteen healthy male volunteers received 50 mg oral doses of acitretin on two occasions, according to a random crossover design. Acitretin was administered during a complete fast or following a moderate breakfast. Plasma samples were obtained at various times and the concentration of acitretin and its 13-cis isomeric metabolite (Ro 13-7652) were quantified by a specific HPLC assay. The AUC0-15 for acitretin was increased when administered with food for all subjects (except one) with a mean increase of 90% (from 1175 to 2249 ng/ml.hr). The maximum plasma concentration of acitretin (Cmax) was increased by 70% when administered with food (from 245 to 416 ng/ml), while the time to reach Cmax was unaffected. The ratio of AUC of Ro 13-7652 to acitretin was the same for both the fasted and fed conditions; therefore, the formation of metabolite was not influenced by concomitant ingestion of food. The presence of food increases the apparent bioavailability of acitretin. A likely mechanism behind this observation is an increase in acitretin solubility in addition to an increase in the lymphatic absorption and a prolonged residence time of the drug in the gastrointestinal tract.

Down's syndrome, hypothyroidism and diabetes mellitus in an adult.

Primary hypothyroidism was diagnosed in a woman aged 33 years, with Down's syndrome and insulin-dependent diabetes mellitus after admission to hospital with hypoglycaemia. The diabetes was stabilized and treatment was commenced with L-thyroxine with a good clinical response. The patient's mother and older sister also had hypothyroidism and all three had no thyroid antibodies. The importance of diagnosing and treating primary hypothyroidism in adult patients with Down's syndrome is stressed even in the absence of thyroid antibodies.