Safety, tolerability, pharmacokinetics, and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers.

RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first-in-human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200-2000 mg). Single oral doses were generally well-tolerated with a predictable safety profile associated with dose-dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half-life ranging 2-6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0-∞ ) increasing proportionally with dose. A pattern of dose and time-dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose-dependent manner with adequate safety and tolerability. Single-dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.

Safety and Pharmacokinetic Characterization of Nacubactam, a Novel ß-Lactamase Inhibitor, Alone and in Combination with Meropenem, in Healthy Volunteers.

Nacubactam is a novel ß-lactamase inhibitor with dual mechanisms of action as an inhibitor of serine ß-lactamases (classes A and C and some class D) and an inhibitor of penicillin binding protein 2 in Enterobacteriaceae The safety, tolerability, and pharmacokinetics of intravenous nacubactam were evaluated in single- and multiple-ascending-dose, placebo-controlled studies. Healthy participants received single ascending doses of nacubactam of 50 to 8,000 mg, multiple ascending doses of nacubactam of 1,000 to 4,000 mg every 8 h (q8h) for up to 7 days, or nacubactam of 2,000 mg plus meropenem of 2,000 mg q8h for 6 days after a 3-day lead-in period. Nacubactam was generally well tolerated, with the most frequently reported adverse events (AEs) being mild to moderate complications associated with intravenous access and headache. There was no apparent relationship between drug dose and the pattern, incidence, or severity of AEs. No clinically relevant dose-related trends were observed in laboratory safety test results. No serious AEs, dose-limiting AEs, or deaths were reported. After single or multiple doses, nacubactam pharmacokinetics appeared linear, and exposure increased in an approximately dose-proportional manner across the dose range investigated. Nacubactam was excreted largely unchanged into urine. Coadministration of nacubactam with meropenem did not significantly alter the pharmacokinetics of either drug. These findings support the continued clinical development of nacubactam and demonstrate the suitability of meropenem as a potential ß-lactam partner for nacubactam. (The studies described in this paper have been registered at ClinicalTrials.gov under NCT02134834 [single ascending dose study] and NCT02972255 [multiple ascending dose study].).

Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector.

BACKGROUND: The anti-interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab. METHODS: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI. RESULTS: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns. CONCLUSIONS: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study. CLINICAL TRIAL REGISTRATION: NCT02678988, NCT02682823.

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.

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.

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.

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.

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 (AUC(0-12)), 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 AUC(0-12), 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 AUC(0-72) 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 AUC(0-72) and by 86% for C(max). In group 3 (n = 13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC(0-96) 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 AUC(0-96) 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.

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.

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.