Scott Fettner

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.

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.

Phase I Evaluation of a 40-kDa Branched-Chain Long-Acting Pegylated IFN-α-2a With and Without Cytarabine in Patients with Chronic Myelogenous Leukemia

Purpose: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-α-2a in which IFN-α 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-α 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 μg/wk to a maximum dose of 630 μg/wk. Sixteen additional patients were treated with escalating doses of PEG-IFN ranging from 450 to 540 μg/wk in combination with two different schedules of low-dose cytarabine (1-β-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 μg/wk. With the addition of ara-C, the DLT was reached at 540 μg/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 (Cmax) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 μg/wk, with no further increases in Cmax 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 μg/wk, showing a dose-related increase in systemic exposure of PEG-IFN. As with Cmax, the AUC did not increase at higher dose levels. The maximum induction (Emax) 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 μg/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-α 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.

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/m2 oxaliplatin, 200 mg/m2 leucovorin, 400 mg/m2 bolus 5-FU, and 400 mg/m2 continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m2 and 5-FU infusion increased to 600 mg/m2; 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/m2 oxaliplatin; 200 mg/m2 leucovorin, 400 mg/m2 bolus 5-FU, and 600 mg/m2 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.

Pharmacokinetics and pharmacodynamics of tocilizumab after subcutaneous administration in patients with rheumatoid arthritis.

OBJECTIVES To investigate the pharmacokinetics, pharmacodynamics, safety and efficacy of subcutaneous tocilizumab 162 mg weekly (QW) or every other week (Q2W) in rheumatoid arthritis patients on methotrexate. METHODS This was a multicenter, open-label, randomized, parallel group study. Patients were randomly assigned to receive tocilizumab 162 mg subcutaneously QW or Q2W for 12 weeks. Pharmacokinetic and pharmacodynamic measurements were taken from baseline through to treatment end. Efficacy was assessed at baseline and Q4W thereafter. Safety and tolerability were monitored. RESULTS 29 patients received tocilizumab treatment for 12 weeks. After final QW and Q2W dosing, mean ± SD for Cmax, Cmin and AUC0-168h/0-336h was 39.4 ± 18.1 and 10.7 ± 6.6 μg/ml, 27.9 ± 14.7 and 2.3 ± 3.2 μg/ml and 5,505 ± 2,632 and 2,332 ± 1,696 μg×h/ml. Median tmax was 2 - 3 days. Mean soluble interleukin-6 receptor (sIL-6R) complex concentration increased within 1 week and plateaued (670 ± 211 (QW); 387 ± 194 ng/ml (Q2W)) by final dosing; median C-reactive protein (CRP) levels decreased to below upper limit of normal after first and third doses; mean ± SD (range) reduction in Disease Activity Score using 28 joints at Week 12 was similar between groups (-2.5 ± 1.2 (-4 to -1); -3.1 ± 1.1 (-5 to -2)). Patients experiencing ≥ 1 adverse event were comparable between groups (71% vs. 80%). CONCLUSIONS Greater tocilizumab exposure and sIL-6R elevation and more rapid CRP level normalization occurred with QW than with Q2W dosing. Both regimens demonstrated clinical benefit and were well tolerated.

Pharmacokinetic Interaction Study of Ritonavir-Boosted Saquinavir in Combination with Rifabutin in Healthy Subjects

ABSTRACT The effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC0-12), maximum observed concentration of drug in plasma (C max), and minimum observed concentration of drug in plasma at the end of the dosing interval (C min) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC0-12, C max, and C min were observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 (n = 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC0-72 and C max of the active moiety (rifabutin plus 25-O-desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC0-72 and by 86% for C max. In group 3 (n = 13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC0-96 and C max of the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC0-96 of rifabutin was not affected, and C max increased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.

Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Tocilizumab in Patients With Rheumatoid Arthritis From 2 Randomized, Controlled Trials: SUMMACTA and BREVACTA

Tocilizumab is a humanized anti–interleukin‐6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24‐week double‐blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2‐compartment population pharmacokinetic model, with first‐order absorption (for subcutaneous) and linear and Michaelis–Menten elimination was used. Mean observed steady‐state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every‐week and every‐2‐week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population‐predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every‐2‐week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every‐2‐week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every‐week subcutaneous and every‐4‐week intravenous regimens and less pronounced with the every‐2‐week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every‐week subcutaneous regimen to the every‐4‐week intravenous regimen and the superiority of the every‐2‐week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.

Assessment of disease-drug-drug interaction between single-dose tocilizumab and oral contraceptives in women with active rheumatoid arthritis.

OBJECTIVES The objective of this study was to evaluate the effect of a single intravenous dose of tocilizumab (TCZ) on pharmacokinetics (PK) of oral contraceptive (OC; norethindrone (NE) and ethinyl estradiol (EE)) and on sex hormone levels (progesterone (PG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)) in subjects with active rheumatoid arthritis (RA) who were on stable doses of methotrexate. METHODS This was an open-label, nonrandomized, multicenter, two-parallel group, one-sequence crossover study. In Group 1, Cycle 1 was a baseline cycle to determine the PK of OC and levels of sex hormones. At the start of Cycle 2, patients continued to receive OC and single TCZ dosing on Day 1. In Cycle 2, we determined the PK of OC and levels of sex hormones when OC and TCZ were combined. In Cycle 3, we determined the PK of OC and the levels of sex hormones after TCZ treatment was stopped. PK for EE and NE were analyzed serially on Day 7 when maximum TCZ effect on inflammation as indicated by C-reactiv protein (CRP) was expected. Hormone levels (PG, LH and FSH) were measured mid-cycle (cycle Days 12 - 16 and Day 21) during each cycle. Group 2 (healthy subjects) was studied to compare the levels of OC PK exposures with those in each cycle of Group 1 (RA subjects). RESULTS Levels of PG, LH and FSH were not affected by the combination of TCZ/OC treatment in RA patients studied. No breakthrough bleeding was attributed to the initiation of TCZ treatment in subjects receiving OCs. PK exposures of EE and NE were similar between RA and healthy subjects at baseline and were not affected by single-dose TCZ. Administration of OC with or without a single dose of TCZ was well tolerated. CONCLUSIONS Data from this study indicated that the PK and sex hormone levels were not affected in RA subjects who had active disease and were on a stable regimen of methotrexate.

A171: Tocilizumab Dosing in Juvenile Idiopathic Arthritis: Optimizing for Different Juvenile Idiopathic Arthritis Type and Patient Body Weight

Tocilizumab (TCZ), an interleukin‐6 receptor (IL‐6R) inhibitor, is effective in systemic and polyarticular juvenile idiopathic arthritis (sJIA, pJIA). Body weight (BW)‐adjusted intravenous dosing regimens (TCZ 8 mg/kg Q2W for sJIA and Q4W for pJIA) were assessed in Japanese phase 3 trials. In Japanese patients (pts), BW adjustment led to lower TCZ exposure with lower BW; thus, higher doses were proposed for pts with BW <30 kg in the global TENDER (sJIA) and CHERISH (pJIA) trials. Herein, we describe the pharmacokinetics (PK), pharmacodynamics (PD), and exposure‐efficacy/‐safety relationships of adjusted BW‐based TCZ therapy in sJIA/pJIA pts.

PReS-FINAL-2159: Tocilizumab (TCZ) dosing in juvenile idiopathic arthritis (JIA): optimising for different JIA type and body weight patients

TCZ, an IL-6R inhibitor, is effective in systemic and polyarticular juvenile idiopathic arthritis (sjia, pjia). BW-adjusted, intravenous dosing regimens (TCZ8 mg/kg Q2W for sjia and Q4W for pjia) were assessed in Japanese phase 3 trials. As shown in Results, BW adjustment led to lower TCZ exposure with lower BW; thus, higher doses were proposed for patients (pts) with BW<30 kg in the global TENDER (sjia) and CHERISH (pjia) trials.