Generics in transplantation medicine: Randomized comparison of innovator and substitution products containing mycophenolate mofetil
.

OBJECTIVE: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. MATERIALS AND METHODS: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. RESULTS: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. CONCLUSION: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.

Tocilizumab has no clinically relevant effects on methotrexate pharmacokinetics in patients with rheumatoid arthritis.

OBJECTIVE: To assess the effects of tocilizumab on methotrexate and 7-hydroxymethotrexate pharmacokinetics in patients with rheumatoid arthritis and to explore the pharmacodynamic effect of tocilizumab on C-reactive protein (CRP), a marker of inflammation. METHODS: Methotrexate (10 - 25 mg) was administered orally on Days 1, 8, 15, 22, 29, 36, and 43. On Day 8 patients received 10 mg/kg tocilizumab intravenously. Blood samples for pharmacokinetic analyses were collected on Days 1, 15, and 43 and for pharmacodynamics (CRP) throughout the study. RESULTS: 90% CIs for mean effect ratios (Day 15/Day 1 and Day 43/Day 1) of methotrexate and 7-hydroxymethotrexate (AUClast and Cmax) were close to or within the bioequivalence boundaries (80 - 125%). CRP normalized within 1 week after tocilizumab injection and remained within normal limits for 3 weeks. CONCLUSION: Tocilizumab and methotrexate can be administered concurrently without dosage adjustments.

Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer.

PURPOSE: Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin. PATIENTS AND METHODS: Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61. RESULTS: During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance. CONCLUSION: There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.

A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS).

OBJECTIVES: Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150mg dose (E150). MATERIALS AND METHODS: Patients with stage IIIB/IV NSCLC (current smokers who failed first-line platinum-based chemotherapy) were randomized to receive E150 or E300 until progression/death/unacceptable toxicity. PRIMARY ENDPOINT: progression-free survival (PFS). Secondary endpoints: overall survival (OS), disease control rate and safety. RESULTS: A total of 342 patients were screened; the intent-to-treat population comprised 159 E300 patients and 154 E150 patients. Median PFS was 7.0 versus 6.9 weeks with E300 versus E150, respectively (unstratified hazard ratio [HR]=1.05, 95% confidence interval [CI]: 0.83-1.33; unstratified log-rank P=0.671). Median OS was 6.8 months in both arms (unstratified HR=1.03, 95% CI: 0.80-1.32; unstratified log-rank P=0.846). Overall, 89.2% (E300 arm) and 84.4% (E150 arm) experienced ≥1 adverse event (AE) of any grade (44.3% and 37%, respectively, experienced grade ≥3 AEs); AEs of special interest were reported in 67.7% and 47.4% of patients, respectively. E300 resulted in higher mean plasma concentrations versus E150, however, this did not improve efficacy. CONCLUSIONS: Despite the difference in erlotinib exposure, there was no evidence of an incremental efficacy benefit of a higher erlotinib dose versus the standard dose in this population of highly active smokers.

Saquinavir 500 mg film-coated tablets demonstrate bioequivalence to saquinavir 200 mg hard capsules when boosted with twice-daily ritonavir in healthy volunteers.

OBJECTIVE: To establish the bioequivalence of a 500 mg film-coated tablet of saquinavir mesylate (FCT SQV) to the 200 mg hard-capsule saquinavir mesylate (HC SQV), both boosted with ritonavir and administered under fed conditions. METHODS: We carried out a multi-centre, open-label, randomized, two-sequence, four-period, two-treatment, replicated crossover study in 93 healthy men and 7 healthy women. Individuals were randomly assigned to receive sequential single doses of saquinavir in one of two treatment sequences: ABAB or BABA. Individuals received 100 mg ritonavir twice daily for 24 days. On days 14,17, 20 and 23, study participants took 1000 mg of HC SQV (five 200 mg capsules, treatment A) or FCT SQV (two 500 mg tablets, treatment B) with a high-fat, high-calorie breakfast, and pharmacokinetic analyses were carried out over the next 24 hours. Area under the saquinavir concentration-time curve (AUC0-alpha), maximum saquinavir plasma concentration (Cmax), time to Cmax and terminal half-life were calculated. The relative bioavailability of FCT SOV versus HC SQV was calculated as the ratio of the respective estimated mean saquinavir AUC0-alpha and Cmax. The calculation was based on an ANOVA including the factors site, sex, sequence, period, treatment and study participant to the log-transformed parameters log(AUC0-alpha) and log(Cmax); the relative bioavailability and the 90% confidence intervals (CIs) were estimated using the treatment contrasts of the ANOVA. Bioequivalence was concluded as for both parameters, AUC0-alpha and Cmax, the 90% CIs for the relative bioavailability were entirely included in the reference region [0.80-1.25]. RESULTS: Saquinavir plasma concentration-time profiles for the two formulations were similar. Geometric mean AUC0-alpha and Cmax values were clearly increased for FCT SQV (26 826 versus 24 430 h*ng/ml; and 3644 versus 3064 ng/ml, respectively); ratios of mean exposures were estimated to be 1.10 for AUC0-alpha and 1.19 for Cmax of saquinavir. However, the corresponding two-sided 90% CIs (1.04-1.16 and 1.14-1.25, respectively) all fell within the limits set for equivalence (0.80, 1.25). The adverse event profile for FCT SQV was similar to that for HC SQV. CONCLUSION: The new 500 mg FCT SQV formulation is bioequivalent to the 200 mg HC SQV formulation, at the dose of 1000 mg, in combination with 100 mg ritonavir under fed conditions. The 500 mg FCT SQV formulation reduces pill count for boosted saquinavir (SQV/r) from six capsules to three tablets twice daily. This may increase patient acceptability of SQV/r, particularly in less treatment-experienced patients.

Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer.

BACKGROUND: Capecitabine (Xeloda) is a novel, oral fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumor tissue via a three-step enzymatic cascade. PURPOSE: The objective of this study was to compare the pharmacokinetics of capecitabine and its metabolites in Japanese and Caucasian cancer patients. METHODS: The study included 20 Japanese and 24 Caucasian patients with breast cancer. All patients received oral capecitabine 825 mg/m(2) twice daily for 14 days, except for study day 1 when only the morning dose was administered. On study days 1 and 14, blood and urine samples were collected after administration of the first dose and at steady state for the evaluation of the pharmacokinetics of capecitabine and its metabolites. The primary pharmacokinetic parameter was AUC(0-infinity ) of 5'-deoxy-5-fluorouridine (5'-DFUR) on day 14. The pharmacokinetic parameters in Japanese and Caucasian patients were compared using an ANOVA with calculation of the 90% confidence interval (CI) for the ratio of the geometric means. RESULTS: Statistical analysis showed equivalence in the AUC of 5'-DFUR on day 14 with a ratio of 1.01 (90% CI 0.85-1.21). Similarly, no relevant influence of race on the pharmacokinetics of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR), or 5-FU was observed. Systemic exposure to alpha-fluoro-beta-alanine (FBAL) was higher in Caucasian than in Japanese patients. On study day 14, both the AUC and the maximum plasma concentration (C(max)) of FBAL were increased by 47% and 33% in Caucasian patients and Japanese patients, respectively. CONCLUSIONS: No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.

Exposure-response relationship of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in a large population of patients with rheumatoid arthritis.

Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid E(max) (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC(50) (concentration at which 50% of E(max) on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.

Exposure-Exposure Relationship of Tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis.

Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid Emax (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC50 (concentration at which 50% of Emax on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity.

Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis.

Tocilizumab is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that has demonstrated efficacy in the treatment of rheumatoid arthritis (RA). A population pharmacokinetic (PK) model was developed using nonlinear mixed effect modeling to describe the PK profile of tocilizumab and used to estimate interindividual variability and assess the influence of covariates on PK parameters. The model was constructed based on data collected from 1793 patients with moderate to severe RA who received tocilizumab (4 or 8 mg/kg), via intravenous infusion every 4 weeks, during 4 phase III clinical trials. Serum concentration-time profiles of tocilizumab were adequately described by a 2-compartment disposition model with parallel linear and nonlinear elimination kinetics. The 8-mg/kg dose of tocilizumab, compared with the 4-mg/kg dose, resulted in a more pronounced saturation of the nonlinear clearance pathway over the dosing interval, and this nonlinear clearance was representative of target-mediated elimination due to tocilizumab binding to the IL-6 receptor.

Unexpected Hepatotoxicity of Rifampin and Saquinavir/Ritonavir in Healthy Male Volunteers.

OBJECTIVES: Rifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers. METHODS: In an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIV-negative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured. RESULTS: In arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (>/= grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations. CONCLUSIONS: Although not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.