Alain Munafo

Influence of interferon β-1a dose frequency on PBMC cytokine secretion and biological effect markers

Interferon-beta regimens for immune-mediated diseases, such as multiple sclerosis (MS), have not been compared regarding their biological effects. In this randomized, parallel-group, placebo-controlled study, cytokine secretion by mitogen-stimulated PBMCs and serum response markers were assessed in volunteers receiving subcutaneous recombinant IFN beta-1a (Rebif, Ares-Serono) 22 microg once a week (QW), 22 microg three times a week, 66 microg QW, or placebo. The production of IL-1beta, IL-6, IFN-gamma, TNF-alpha and TNF-beta markedly decreased during 24-48 h after each injection, with limited dose-dependency and no evidence of tolerance or effect augmentation over 1 month. IL-10 secretion remained unchanged. The increase in serum beta2-microglobulin, neopterin and 2-5A-synthetase was more sustained. Thus, IFN-beta-induced immunomodulation in vivo strongly depends on the administration schedule, the time-integrated effect being 2-3 times greater when a same weekly dose is divided in three injections.

Pharmacokinetics and Pharmacodynamics of IFN-β1a in Healthy Volunteers

The pharmacokinetics of recombinant human interferon-β1a (IFN-β1a) (Rebif, Ares-Serono, Geneva, Switzerland) were investigated in healthy volunteers following intravenous (i.v.) administration of increasing single doses of the drug (22 μg/6 million international units [MIU], 44 μg/12 MIU, and 66 μg/18 MIU); i.v., intramuscular (i.m.), and subcutaneous (s.c.) administration of a 66-μg dose; and repeated s.c. administration of four 66-μg doses at 48-h intervals. The disposition of IFN-β1a followed triexponential decay after i.v. administration (half-lives 3 min, 42 min, and 22 h, respectively). After s.c. and i.m. administration, absorption was the rate-limiting factor in the terminal phase. The median absolute bioavailabilities were 30% and 27%, respectively. The accumulation ratio after repeated s.c. injections was 2.4, and a terminal half-life of 66 h was observed. Intracellular 2-5A synthetase activity and serum neopterin and β2-microglobulin concentrations increased after all IFN-β1a injections and rem...

Pharmacokinetics and Biological Activity of Atacicept in Patients With Rheumatoid Arthritis

Atacicept is a recombinant fusion protein containing the extracellular ligand‐binding portion of the transmembrane activator and CAML interactor (TACI, CD267) receptor and inhibits B lymphocyte stimulator (BLyS, CD257) and a proliferation‐inducing ligand (APRIL, CD256), both potent stimulators of B cell maturation, proliferation, and survival. Atacicept pharmacokinetics and pharmacodynamics were assessed in a double‐blind, placebo‐controlled, phase I study in patients with active, moderate to severe rheumatoid arthritis receiving atacicept either as a single subcutaneous or repeated, every other week dose. Pharmacokinetic profiles were determined by measuring serum concentrations of free atacicept and its complex with BLyS. Nonspecific immunoglobulin (Ig)M, IgG, and IgA; IgM‐RF (rheumatoid factor), IgG‐RF, and IgA‐RF antibody levels; and B cell profiles provided markers of biological activity. Pharmacokinetic, biological activity, and relationships between atacicept dose and Ig antibody response were evaluated. Pharmacokinetic profiles of atacicept were nonlinear, influenced by saturable binding with its ligands, but were consistent and predictable. Atacicept treatment reduced Ig and RF serum concentration. IgM antibody levels were most sensitive to atacicept, followed by IgA and IgG, underlining the biological activity of atacicept in patients with rheumatoid arthritis. These findings can be used to explore dosing regimen design scenarios in future studies.

Sinistrin Clearance for Determination of Glomerular Filtration Rate: A Reappraisal of Various Approaches Using a New Analytical Method

Several approaches are available to estimate the glomerular filtration rate (GFR) from the sinistrin clearance. To compare such approaches, GFR was estimated in six healthy volunteers, both after a bolus injection and a bolus dose followed by a 6‐hour infusion. A recently developed high‐performance liquid chromatography method was used for the determination of sinistrin levels, enabling precise measurements in plasma and urine samples with high sensitivity. Blood and urine were sampled up to 6 hours. Four calculation methods for estimating GFR were applied: 1) classical ratio of urinary excretion rate over plasma concentration (UV/P); 2) two‐point (log‐linear regression slope times monocompartmental volume of distribution) after bolus; 3) ratio of dose over area under the curve (D/AUC) after bolus; and 4) ratio of infusion rate over steady‐state concentration during infusion (Rinf/P). The results obtained by fitting a pharmacokinetic model to all the plasma and urine data served as the standard against which the performance of the respective calculation methods were examined. The UV/P method performed poorly on bolus data, mainly by underestimating GFR at late times; on both bolus and infusion data, it suffered from important imprecisions on the urinary volume. The two‐point method appeared applicable only between 2 and 4 hours after the bolus dose. The D/AUC method with extrapolation to infinity was highly reliable when integrating the concentrations up to 3 hours or more after the bolus dose. The Rinf/P method was satisfactory if applied later than 2 to 3 hours after the loading dose. The advantages and drawbacks of each method have to be evaluated in relation to the particular clinical setting in which GFR is to be estimated.

Pharmacokinetics and immunoglobulin response of subcutaneous and intravenous atacicept in patients with systemic lupus erythematosus

Atacicept, a recombinant fusion protein of the TACI receptor and human IgG, is an inhibitor of B-Lymphocyte Stimulator (BLyS) and APRIL, potent stimulators of B cell maturation, proliferation, and survival. Pharmacokinetics (PKs) and biological activity of intravenous (iv) and subcutaneous (sc) atacicept are described here for patients with systemic lupus erythematosus in two randomized, double-blind, placebo-controlled, Phase Ib studies. Study 1: Six cohorts of eight patients received sc atacicept (single dose: 0.3, 1, 3, or 9 mg/kg; four weekly doses: 1 or 3 mg/kg), or placebo (3:1 ratio). Study 2: Four cohorts of six patients received iv atacicept (single dose: 3, 9, or 18 mg/kg; multiple dose: 2 x 9 mg/kg), or matching placebo (5:1 ratio). PK profiles were determined through serum atacicept and atacicept-BLyS complex, and biological activity through IgA, IgG, and IgM levels. PK profiles of atacicept were influenced by saturable binding between atacicept and its ligands, and were consistent and predictable across doses and regimens. Atacicepts biological activity was compatible with its presumed mechanism of action. Bioavailability was approximately 30-40% following sc or iv administration and similar doses yielded similar biological activity irrespective of administration route. This observation may have a mechanistic foundation and may inform dosing regimen design for future studies.

The effect of a low dose of quinidine on the disposition of flecainide in healthy volunteers.

SummaryWe have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i. v. infusion over 30 min.Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.41·kg−1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml·min−1·kg−1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml·min−1·kg−1). The excretion of the metabolites of flecainide over 48 h was significantly reduced.These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml·min−1·kg−1).The effects of flecainide on ECG intervals were not altered by quinidine.Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.

Application of Item Response Theory to Modeling of Expanded Disability Status Scale in Multiple Sclerosis

ABSTRACTIn this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients’ (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time, and the model was then extended to cladribine arms to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. The IRT model was able to describe baseline and longitudinal EDSS data on item and total level. The final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of eight items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modeling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.

Resistance Development: A Major Piece in the Jigsaw Puzzle of Tumor Size Modeling

Mathematical models of tumor size (TS) dynamics and tumor growth inhibition (TGI) need to place more emphasis on resistance development, given its relevant implications for clinical outcomes. A deeper understanding of the underlying processes, and effective data integration at different complexity levels, can foster the incorporation of new mechanistic aspects into modeling approaches, improving anticancer drug effect prediction. As such, we propose a general framework for developing future semi‐mechanistic TS/TGI models of drug resistance.

Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials

The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting‐relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC‐related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit‐linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC‐derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism‐specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.

Correction to: The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis

The cladribine prodrug is phosphorylated intracellularly to its active product, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), by deoxycytidine kinase.