Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO.

RATIONALE: Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia. OBJECTIVE: The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia. METHODS: Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations. RESULTS: A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing. CONCLUSION: This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

Effect of erlotinib on CYP3A activity, evaluated in vitro and by dual probes in patients with cancer.

In vitro, erlotinib (0-30 µmol/l) and C-labelled midazolam (MDZ) (5 µmol/l) were incubated with human liver microsomes; separately, microsomes were preincubated with erlotinib (10 µmol/l) before the addition of MDZ. Results showed a time-dependent inhibition of MDZ metabolism by erlotinib, with a Ki of 7.5 µmol/l and an inactivation rate constant of 0.009/min. Patients with cancer (n=24) received a single oral dose of 7.5 mg MDZ and a single intravenous dose of 3 µCi [C-N-methyl] erythromycin on days 1, 8, 14 and 21. Patients also received 150 mg oral erlotinib daily from day 8 to day 14. Plasma concentrations of erlotinib and OSI-420 were determined on days 8 and 14; MDZ and 1'-hydroxymidazolam were determined on days 1, 8, 14 and 21. Coadministration of erlotinib resulted in a 4 and a 16% increase in CO2 on days 8 and 14, respectively, after the administration of erythromycin. The mean AUC0-last of MDZ decreased 17 and 34% after erlotinib treatment on day 8 and day 14, respectively. The half-life of MDZ and the AUC ratio of 1'-hydroxymidazolam to MDZ were not significantly changed. Although erlotinib may be a weak mechanism-based irreversible inhibitor of CYP3A4 in vitro, in vivo, erlotinib did not inhibit CYP3A-mediated metabolism, as determined by the erythromycin breath test and the MDZ pharmacokinetics. The mechanism for reduced exposure of MDZ is unclear, but may be because of an increase in intestinal metabolism or decreased absorption. These findings suggest that coadministration of erlotinib may not result in clinically relevant increases in exposure of CYP3A substrates.

The effect of rifampicin, a prototypical CYP3A4 inducer, on erlotinib pharmacokinetics in healthy subjects.

PURPOSE: Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib. METHODS: Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8-14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8-18. The primary endpoint in each study was the ratio of exposure (AUC0-∞ and C max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only. RESULTS: In Study 1, the geometric mean ratios of AUC0-∞ and C max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC0-∞ and C max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1. CONCLUSIONS: Erlotinib exposure (AUC0-∞ and C max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.

Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: a dose-escalation study.

Capecitabine added to docetaxel extends survival in metastatic breast cancer (MBC) and shows additive efficacy with erlotinib in pre-clinical studies. This study aimed to determine the maximum-tolerated dose (MTD) of capecitabine/docetaxel with erlotinib and assess tolerability, anti-tumour activity and potential pharmacokinetic interactions. Three treatment cohorts were assessed, using different dosing regimens. A total of 24 women with MBC were enrolled sequentially. The regimen comprising erlotinib 100mg/day continuously, capecitabine 825mg/m2 bid on days 1 to 14 and docetaxel 75mg/m2 intravenously every 3 weeks on day 1 was well tolerated and was established as the MTD. Overall response rate was 67%, comprising two complete and 12 partial responders in 21 assessable patients. The most common treatment-related adverse events were gastrointestinal disorders and skin toxicities. Pharmacokinetic studies showed that exposure to the three drugs was not reduced when given in combination. These encouraging preliminary results warrant further trials of the combination in MBC.

Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals.

The effects of food on the pharmacokinetics of erlotinib were investigated in two open-label, randomized studies. In a single-dose crossover study (n = 18), 150 mg of erlotinib was administered under either fasting or fed conditions. In the first period, an approximate doubling in the area under the plasma concentration-time curve was evidenced by the geometric mean ratio (GMR) of 2.09 observed under fed conditions; whereas, in the second period there was a decrease, with a GMR of 0.93. In a multiple-dose parallel study (n = 22), 100 mg of erlotinib was administered daily for 8 days, either 7 days of fasting followed by feeding on day 8, or the reverse sequence. In this study, food resulted in an increase in the plasma concentration-time curve on day 1, with a GMR of 1.66 (P = 0.015). In contrast, there was only a 37% increase on day 7, with a GMR of 1.34 (P = 0.252). These studies indicate that food can substantially increase plasma exposure to erlotinib. Given the maximum tolerated dose of erlotinib used in clinical practice, we recommend that erlotinib be taken under conditions of fasting.

The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition.

BACKGROUND: Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed that erlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2. METHODS: A computer-based simulation model, SimCYP, predicted that CYP3A4 contributed to approximately 70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other approximately 30%. A drug-drug interaction study was therefore conducted for erlotinib and a potent CYP3A4 inhibitor, ketoconazole, in healthy male volunteers to evaluate the impact of CYP3A4 inhibition on erlotinib exposure. RESULTS: Ketoconazole caused an almost two-fold increase in erlotinib plasma area under the concentration curve and in maximum plasma concentration. This is consistent with the SimCYP prediction of a two-fold increase in erlotinib AUC, further validating a primary (approximately 70%) role of CYP3A4 in erlotinib elimination. CONCLUSION: Prediction of clinically important drug-drug interaction with SimCYP using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.

Phase 1b dose escalation study of erlotinib in combination with infusional 5-Fluorouracil, leucovorin, and oxaliplatin in patients with advanced solid tumors.

PURPOSE: Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m(2) oxaliplatin, 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 400 mg/m(2) continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m(2) and 5-FU infusion increased to 600 mg/m(2); and cohort 3: erlotinib increased to 150 mg/d). RESULTS: Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease. CONCLUSIONS: The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m(2) oxaliplatin; 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 600 mg/m(2) infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.

Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer.

OBJECTIVE: Our objective was to assess the pharmacokinetics of erlotinib in a large patient population with solid tumors, identify covariates, and explore relationships between exposure and safety outcomes (rash and diarrhea) in patients with non-small cell lung cancer receiving single-agent erlotinib. METHODS: The population pharmacokinetic analysis was performed by use of NONMEM based on 4068 concentration samples from 1047 patients receiving erlotinib as a single agent or in combination with chemotherapy. By use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on clearance and volume was examined. Spearman rank correlation analyses were performed to test for correlations between maximum grades of rash and diarrhea and erlotinib exposure in non-small cell lung cancer patients treated with single-agent erlotinib. RESULTS: On the basis of the final model developed from patients treated with erlotinib as a single agent, the oral clearance was 3.95 L/h, the oral volume of distribution was 233 L, and the absorption rate was 0.95 h(-1). The median erlotinib half-life based on this patient population was 36.2 hours. Total bilirubin, alpha1-acid glycoprotein, and smoking status were the most important factors affecting clearance. The clearance in current smokers was 24% faster than that in former smokers or those who never smoked. There was a statistically significant correlation between drug exposure and rash (P < .05). However, there was significant overlap in the range of values for patients who had no rash (grade = 0) and those who had any grade of rash. No significant correlation was found between exposure and diarrhea. CONCLUSIONS: The long half-life of erlotinib supports the current once-daily dosing regimen at 150 mg/d. Effects of covariates on erlotinib clearance and correlations with adverse event severity were provided to aid in the detection of a treatment-emergent effect.

Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects.

A randomized, open-label, 2-period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150-mg tablet versus a 25-mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI-420, were measured after each dose. The ratios of geometric means for AUC(0-infinity) and Cmax of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%-63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150-mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.

Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers.

Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers after a single oral dose of [14C]erlotinib hydrochloride (100-mg free base equivalent, approximately 91 microCi/subject). The mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The majority of the total administered radioactivity was excreted in feces (83+/-6.8%), and only a low percentage of the dose was recovered in urine (8.1+/-2.8%). Only less than 2% of what was recovered in humans was unchanged erlotinib, which demonstrates that erlotinib is eliminated predominantly by metabolism. In plasma, unchanged erlotinib represented the major circulating component, with the pharmacologically active metabolite M14 accounting for approximately 5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib are O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, and conjugation of the oxidative metabolites with glucuronic acid (M3, M8, and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.

Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-alpha-2a with and without cytarabine in patients with chronic myelogenous leukemia.

PURPOSE: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-alpha-2a in which IFN-alpha is attached to a branched methoxypolyethylene glycol (PEG) moiety of large molecular weight (40 kDa). Such molecular modification results in sustained absorption after s.c. drug administration and a prolonged half-life. A phase I study of PEG-IFN was conducted in patients with chronic myelogenous leukemia (CML) who were previously treated with IFN-alpha to evaluate the effect of sustained exposure to IFN on patients with CML. EXPERIMENTAL DESIGN: Twenty-seven patients with long-term or IFN-refractory CML were enrolled in cohorts of three or six patients. PEG-IFN was given once weekly by s.c. injections starting at a dose of 270 microg/wk to a maximum dose of 630 microg/wk. Sixteen additional patients were treated with escalating doses of PEG-IFN ranging from 450 to 540 microg/wk in combination with two different schedules of low-dose cytarabine (1-beta-D-arabinofuranosylcytosine, ara-C). Serial venous blood samples were collected to evaluate the pharmacokinetic and pharmacodynamic characteristics of PEG-IFN in these patients. RESULTS: The dose-limiting toxicity (DLT) as defined by the protocol was not achieved at the highest dose tested of 630 mug/wk. With the addition of ara-C, the DLT was reached at 540 microg/wk. The safety profile was similar to that of unmodified IFNs. Of 27 patients treated with PEG-IFN, 14 (52%) achieved or maintained a complete hematologic response and three (11%) achieved a complete cytogenetic response. Among 16 patients treated with the combination of PEG-IFN and ara-C, 11 (69%) achieved or maintained complete hematologic remission and two (13%) achieved complete cytogenetic remission. The mean serum peak concentration (C(max)) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 microg/wk, with no further increases in C(max) at higher dose levels. Serum concentration reached peak value starting about 48 hours after drug administration and was maintained at close to peak value throughout the dosing interval. The mean +/- SD area under the serum concentration-time curve (AUC) calculated after the first dose also increased from 1,022 +/- 694 to 3,343 +/- 2,728 ng hour/mL as dose was increased from 270 to 450 microg/wk, showing a dose-related increase in systemic exposure of PEG-IFN. As with C(max), the AUC did not increase at higher dose levels. The maximum induction (E(max)) of neopterin, the surrogate marker of the pharmacodynamic activity of PEG-IFN, increased from 120% to 361% over baseline values as the dose was increased from 270 to 540 microg/wk. On the once-weekly multiple dosing schedule, both the PEG-IFN and neopterin concentration seemed to reach steady state by week 5 and the steady-state values were maintained with chronic dosing over 6 months. CONCLUSION: Pegasys provided a significant advantage over standard IFN-alpha by enabling once-weekly dosing while maintaining acceptable safety, tolerability, and activity profiles. This branched 40-kDa PEG-IFN was well tolerated both as a monotherapy as well as in combination with ara-C. Demonstration of its sustained exposure, pharmacodynamic activity, hematologic response, and evidence of cytogenetic response in several patients in this limited study with either IFN-refractory or INF-intolerant patients provides a promise for further investigation in combination with new agents like imatinib.