Methotrexate Dose in Patients With Early Rheumatoid Arthritis Impacts Methotrexate Polyglutamate Pharmacokinetics, Adalimumab Pharmacokinetics, and Efficacy: Pharmacokinetic and Exposure-response Analysis of the CONCERTO Trial.

PURPOSE: Methotrexate (MTX) and adalimumab are well-recognized treatments of rheumatoid arthritis (RA), the efficacy of which may be driven by intracellular polyglutamates (PGs). The aim of this analysis was to characterize MTX PG concentrations and adalimumab pharmacokinetics in the CONCERTO trial. In addition, the relationships between MTX dose/pharmacokinetics, adalimumab pharmacokinetics, and efficacy were evaluated. METHODS: CONCERTO was a double-blind, parallel-arm study in patients with early RA randomized to adalimumab 40 mg SC every other week plus blinded MTX 2.5, 5, 10, or 20 mg PO once weekly, for 26 weeks. Blood samples were obtained through week 26 for the determination of concentrations of MTX PG, adalimumab, and anti-adalimumab antibody (AAA). Clinical outcomes were also assessed. FINDINGS: A total of 395 patients were included in the analysis (MTX, 329; adalimumab, 395). The mean time to steady-state MTX PG concentration was increased with MTX dose, from 8 to >26 weeks, depending on PG chain length. Dose proportionality changed with PG chain length. As MTX dose was increased, the percentage of short-chain PGs increased less than dose proportionally, while the percentage of long-chain PGs increased more than dose proportionally. For very-long-chain PGs, dose proportionality could not be assessed due to the nonmeasurable concentrations in the 2.5- and 5-mg MTX dose groups. As MTX dose increased, mean adalimumab concentrations also increased (P < 0.001). The percentage of patients with AAA decreased with increasing MTX dose, and at week 26, AAA+ status was significantly correlated with MTX dose level (P = 0.005). In general, rates of response, defined using the 28-joint count disease activity score based on C-reactive protein (DAS28[CRP]; response, <3.2), were greater in the subgroup without AAA. The likelihood of a patient achieving a DAS28(CRP) response was related to the baseline measurement (P < 0.001) and to the concentration of adalimumab (P = 0.001), but not to the MTX regimen (P = 0.689). IMPLICATIONS: The dose-response characteristics of MTX PG pharmacokinetics and the resultant effects of MTX on adalimumab exposures should be considered when determining the benefit-risk profile of MTX and adalimumab combination therapy in patients with early RA. ClinicalTrials.gov identifier: NCT01185301.

Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab.

BACKGROUND: Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials. METHODS: Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label. RESULTS: In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation. CONCLUSION: In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients. TRIAL REGISTRATION NUMBER: MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

Methotrexate Dosage Reduction Upon Adalimumab Initiation: Clinical and Ultrasonographic Outcomes from the Randomized Noninferiority MUSICA Trial.

OBJECTIVE: To examine the clinical and ultrasonographic (US) outcomes of reducing methotrexate (MTX) dosage upon initiating adalimumab (ADA) in MTX-inadequate responders with moderately to severely active rheumatoid arthritis (RA). METHODS: MUSICA (NCT01185288) was a double-blind, randomized, parallel-arm study of 309 patients with RA receiving MTX ≥ 15 mg/week for ≥ 12 weeks before screening. Patients were randomized to high dosage (20 mg/week) or low dosage (7.5 mg/week) MTX; all patients received 40 mg open-label ADA every other week for 24 weeks. The primary endpoint was Week 24 mean 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) to test for noninferiority of low-dosage MTX using a 15% margin. US images were scored using a 10-joint semiquantitative system incorporating OMERACT definitions for pathology, assessing synovial hypertrophy, vascularity, and bony erosions. RESULTS: Rapid improvement in clinical indices was observed in both groups after addition of ADA. The difference in mean DAS28-CRP (0.37, 95% CI 0.07-0.66) comparing low-dosage (4.12, 95% CI 3.88-4.34) versus high-dosage MTX (3.75, 95% CI 3.52-3.97) was statistically significant and non-inferiority was not met. Statistically significant differences were not detected for most clinical, functional, and US outcomes. Pharmacokinetic and safety profiles were similar. CONCLUSION: In MUSICA, Week 24 mean DAS28-CRP, the primary endpoint, did not meet non-inferiority for the low-dosage MTX group. Although the differences between the 2 MTX dosage groups were small, our study findings did not support routine MTX reduction in MTX inadequate responders initiating ADA.

Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial.

OBJECTIVE: CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA). METHODS: Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance. RESULTS: Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose. CONCLUSIONS: Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent.

A double-blind, randomized, placebo-controlled study of the dopamine D3 receptor antagonist ABT-925 in patients with acute schizophrenia.

There is substantial preclinical and clinical evidence to suggest a potential role for the dopamine D3 receptor in the treatment of schizophrenia. ABT-925 is a selective dopamine D3 receptor antagonist with an approximately 100-fold higher in vitro affinity for dopamine D3 versus D2 receptors. This double-blind, randomized, placebo-controlled, escalating-dose, parallel-group study assessed the efficacy and safety of ABT-925 in the treatment of patients with acute exacerbation of schizophrenia. One hundred fifty-five patients were assessed over a 6-week double-blind treatment period (placebo: n = 48; ABT-925 50 mg once daily [QD]: n = 53; ABT-925 150 mg QD: n = 54). The primary efficacy measure was mean change from baseline to final evaluation on the Positive and Negative Syndrome Scale total score. Secondary measures of efficacy and pharmacokinetic parameters were also assessed. Safety assessments included adverse event monitoring, laboratory tests, vital signs, movement rating scales, and electrocardiogram measures. No statistically significant treatment effect was observed with ABT-925 50 mg QD or 150 mg QD compared with placebo on primary or secondary efficacy end points. Pharmacokinetic parameter estimates increased with dose in a linear fashion. ABT-925 50 mg QD and 150 mg QD were generally well tolerated, with adverse event profiles similar to that of placebo. Findings from a concurrent positron emission tomography study among healthy volunteers suggest that the ABT-925 doses used in this study may not have been sufficient to adequately occupy D3 receptors, thereby underscoring the importance of pharmacodynamic markers, such as PET, in determining appropriate compound doses before embarking on studies in a target population.

Determination of calcium salt solubility with changes in pH and P(CO(2)), simulating varying gastrointestinal environments.

The amount of calcium available for absorption is dependent, in part, on its sustained solubility in the gastrointestinal (GI) tract. Many calcium salts, which are the calcium sources in supplements and food, have pH-dependent solubility and may have limited availability in the small intestine, the major site of absorption. The equilibrium solubility of four calcium salts (calcium oxalate hydrate, calcium citrate tetrahydrate, calcium phosphate, calcium glycerophosphate) were determined at controlled pH values (7.5, 6.0, 4.5 and < or = 3.0) and in distilled water. The solubility of calcium carbonate was also measured at pH 7.5, 6.0 and 4.5 with two CO(2) environments (0.3 and 152 mmHg) above the solution. The precipitation profile of CaCO(3) was calculated using in-vivo data for bicarbonate and pH from literature and equilibrium calculations. As pH increased, the solubility of each calcium salt increased. However, in distilled water each salt produced a different pH, affecting its solubility value. Although calcium citrate does have a higher solubility than CaCO(3) in water, there is little difference when the pH is controlled at pH 7.5. The partial pressure of CO(2) also played a role in calcium carbonate solubility, depressing the solubility at pH 7.5. The calculations of soluble calcium resulted in profiles of available calcium, which agreed with previously published in-vivo data on absorbed calcium. The experimental data illustrate the impact of pH and CO(2) on the solubility of many calcium salts in the presence of bicarbonate secretions in the intestine. Calculated profiles using in-vivo calcium and bicarbonate concentrations demonstrate that large calcium doses may not further increase intestinal calcium absorption once the calcium carbonate solubility product has been reached.

Use of a physiologic bicarbonate buffer system for dissolution characterization of ionizable drugs.

PURPOSE: The aim of this study was to examine if sparging with CO2(g) could be used to establish stable biorelevant bicarbonate buffers, in aqueous medium, for use in dissolution characterization of low-solubility ionizable drugs. METHODS: Preparation of the bicarbonate-containing dissolution medium was monitored by use of a commercially available fiberoptic probe to measure the concentration of dissolved CO2(aq). Intrinsic dissolution measurements at 100 rpm, 37 degrees C for indomethacin and dipyridamole were performed using a rotating disk and UV detection at pH 6.8 and 5.0 in a USP dissolution vessel apparatus. RESULTS: Indomethacin dissolution at pH 6.8 was significantly impacted by the concentration of CO2(g) in the sparging gas. Dipyridamole flux at pH 6.8 was independent of buffer species or buffer concentrations studied. However, dipyridamole dissolution at pH 5 was also a strong function of the concentration of CO2(g) in the sparging gas. CONCLUSIONS: Stable bicarbonate biorelevant buffers could be established to perform intrinsic dissolution rate determinations for indomethacin and dipyridamole as long a continuous gas sparging of CO2(g) was used. Depending of the pH of the dissolution medium, the intrinsic dissolution rates of both indomethacin and dipyridamole were affected by the bicarbonate concentration. Sparging with CO2(g) to create physiologic buffers has a unique advantage over conventional buffers in that gas sparging serves as a continuous source of bicarbonate buffer species. This advantage was demonstrated by performing dissolution experiments at pH values typically associated with the fed state (pH 5) and applying relatively low CO2(g) pressures, resulting in bicarbonate concentrations less than 0.5 mM. It was demonstrated that CO2(g) sparging at a pH consistent with the fed state created an in-situ bicarbonate buffer at low concentrations, which had a significant impact on the dissolution of a basic drug such as dipyridamole.