Felix Waldmeier

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (tmax 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ± 0.095 μg/ml (mean ± S.D., n = 4) for imatinib and 0.115 ± 0.026 μg/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ± 0.9 h for imatinib, 20.6 ± 1.7 h for CGP74588, and 57.3 ± 12.5 h for 14C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

The Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Varying Degrees of Renal Function

An open‐label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometaθ) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50–80 mL/min), or moderately/severely impaired (CLcr = 10–50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1‐month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C‐labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C‐telopeptide and N‐telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.

Absorption, distribution, metabolism and elimination of the direct renin inhibitor aliskiren in healthy volunteers

Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [14C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (Cmax) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC0–∞), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.

Pharmacokinetics, Distribution, Metabolism, and Excretion of Deferasirox and Its Iron Complex in Rats

Deferasirox (Exjade, ICL670, CGP72670) is an iron-chelating drug for p.o. treatment of transfusional iron overload in patients with β-thalassemia or sickle cell disease. The pharmacokinetics and disposition of deferasirox were investigated in rats. The animals received single intravenous (10 mg/kg) or p.o. (10 or 100 mg/kg) doses of 14C-radiolabeled deferasirox. Biological samples were analyzed for radioactivity (liquid scintillation counting, quantitative whole-body autoradioluminography), for deferasirox and its iron complex [high-performance liquid chromatography (HPLC)/UV], and for metabolites (HPLC with radiodetection, liquid chromatography/mass spectrometry, 1H and 13C NMR, and two-dimensional NMR techniques). At least 75% of p.o.-dosed deferasirox was absorbed. The p.o. bioavailability was 26% at the 10 mg/kg dose and showed an overproportional increase at the 100 mg/kg dose, probably because of saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs, and gastrointestinal tract. Enterohepatic recirculation of deferasirox was observed. No retention occurred in any tissue. The placental barrier was passed to a low extent. Approximately 3% of the dose was transferred into the breast milk. Excretion of deferasirox and metabolites was rapid and complete within 7 days. Key clearance processes were hepatic metabolism and biliary elimination via multidrug resistance protein 2. Deferasirox, iron complex, and metabolites were excreted largely via bile and feces (total ≥90%). Metabolism included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.

Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state.

Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult β-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (∼20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5′-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).

Metabolism and Disposition of Vatalanib (PTK787/ZK-222584) in Cancer Patients

Vatalanib (PTK787/ZK-222584) is a new oral antiangiogenic molecule that inhibits all known vascular endothelial growth factor receptors. Vatalanib is under investigation for the treatment of solid tumors. Disposition and biotransformation of vatalanib were studied in an open-label, single-center study in patients with advanced cancer. Seven patients were given a single oral 14C-radiolabeled dose of 1000 mg of vatalanib administered at steady state, obtained after 14 consecutive daily oral doses of 1000 mg of nonradiolabeled vatalanib. Plasma, urine, and feces were analyzed for radioactivity, vatalanib, and its metabolites. Metabolite patterns were determined by high-performance liquid chromatography coupled to radioactivity detection with off-line microplate solid scintillation counting and characterized by LC-MS. Vatalanib was well tolerated. The majority of adverse effects corresponded to common toxicity criteria grade 1 or 2. Two patients had stable disease for at least 7 months. Plasma Cmax values of 14C radioactivity (38.3 ± 26.0 μM; mean ± S.D., n = 7) and vatalanib (15.8 ± 9.5 μM) were reached after 2 and 1.5 h (median), respectively, indicating rapid onset of absorption. Terminal elimination half-lives in plasma were 23.4 ± 5.5 h for 14C radioactivity and 4.6 ± 1.1 h for vatalanib. Vatalanib cleared mainly through oxidative metabolism. Two pharmacologically inactive metabolites, CGP-84368/ZK-260120 [(4-chlorophenyl)-[4-(1-oxy-pyridin-4-yl-methyl)-phthalazin-1-yl]-amine] and NVP-AAW378/ZK-261557 [rac-4-[(4-chloro-phenyl)amino]-α-(1-oxido-4-pyridyl)phthalazine-1-methanol], having systemic exposure comparable to that of vatalanib, contributed mainly to the total systemic exposure. Vatalanib and its metabolites were excreted rapidly and mainly via the biliary-fecal route. Excretion of radioactivity was largely complete, with a radiocarbon recovery between 67% and 96% of dose within 7 days (42–74% in feces, 13–29% in urine).

Pharmacokinetics and metabolism of formestane in breast cancer patients

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.

PIMECROLIMUS: ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION IN HEALTHY VOLUNTEERS AFTER A SINGLE ORAL DOSE AND SUPPLEMENTARY INVESTIGATIONS IN VITRO

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [3H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After tmax (1–3 h), its blood concentrations fell quickly to 3% of Cmax at 24 h, followed by a slow terminal elimination phase (average t1/2 62 h). Radioactivity in blood decreased more slowly (8% of Cmax at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve0–24 h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus.

Percutaneous Absorption of Pimecrolimus Is Not Increased in Patients with Moderate to Severe Atopic Dermatitis when Pimecrolimus Cream 1% Is Applied under Occlusion

Aim: To evaluate the systemic exposure of pimecrolimus cream 1% applied under occlusion in atopic dermatitis (AD) patients. Methods: A noncomparative, open-label study conducted in 3 groups of moderate to severe AD patients: A (adults, n = 9), B (adolescents, n = 4) and C (children, n = 6). Pimecrolimus cream 1% was applied twice daily for 8.5 days with overnight occlusion in patients with investigator’s global assessment scores of ≧3 and AD involving at least 30% of their body surface area. Pimecrolimus blood concentrations were analyzed. Results: The highest pimecrolimus blood concentrations observed in adults, adolescents and children were 1.84, 0.55 and 1.29 ng/ml, respectively. Pimecrolimus blood concentrations and affected body surface area showed no apparent correlation. Conclusion: No measurable differences were found in pimecrolimus blood concentrations, efficacy and safety profile when pimecrolimus cream 1% was applied under occlusion versus application without occlusion. These findings reflect the high lipophilic properties of pimecrolimus.

Metabolism and disposition of the oral absorption enhancer 14C-radiolabeled 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC) in healthy postmenopausal women and supplementary investigations in vitro.

8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC), a compound lacking pharmacological activity enhances the absorption of salmon calcitonin, when co-administered. Disposition and biotransformation of 5-CNAC was studied in six healthy postmenopausal women following a single oral dose of 200mg (14)C-radiolabeled 5-CNAC (as disodium monohydrate salt). Blood, plasma, urine and feces collected over 7 days were analyzed for radioactivity. Metabolite profiles were determined in plasma and excreta and metabolite structures were elucidated by LC-MS/MS, LC-(1)H NMR, enzymatic methods and by comparison with reference compounds. Oral 5-CNAC was safe and well tolerated in this study population. 5-CNAC absorption was rapid (t(max)=0.5h; C(max)=9.00 ± 2.74 μM (mean ± SD, n=6) and almost complete. The elimination half-life (t(½)) was 1.5 ± 1.1h. The radioactive dose was excreted mainly in urine (≥ 90%) in form of metabolites and 0.071% as intact 5-CNAC. Excretion of radioactivity in feces was minor and mostly as metabolites (<3%). Radioactivity in plasma reached C(max) (35.4 ± 7.9 μM) at 0.75 h and declined with a half-life of 13.9 ± 4.3h. 5-CNAC accounted for 5.8% of the plasma radioactivity AUC(0-24h). 5-CNAC was rapidly cleared from the systemic circulation, primarily by metabolism. Biotransformation of 5-CNAC involved: (a) stepwise degradation of the octanoic acid side chain and (b) conjugation of 5-CNAC and metabolites with glucuronic acid at the 2-phenolic hydroxyl group. The metabolism of 5-CNAC in vivo could be reproduced in vitro in human hepatocytes. No metabolism of 5-CNAC was observed in human liver microsomes.