The population pharmacokinetics of ustekinumab are characterized in patients with moderate to severe plaque psoriasis in 2 Phase 3 studies (PHOENIX 1 and PHOENIX 2). Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent volume of distribution, and absorption rate constant from the final covariate model are 0.465 L.day(-1) (2.0%), 15.7 L (2.0%), and 0.354 day(-1) (16.2%), respectively. The interindividual variabilities for apparent clearance and apparent volume of distribution are 41.0% and 33.2%, respectively. Of the factors evaluated in this analysis, body weight, diabetes, and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and/or apparent volume of distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.

1. Metabolism of the analgesic agent tramadol hydrochloride has been investigated after a single oral administration of tramadol to three male volunteers (100 mg/subject), and a urine pool (4-12h) was obtained. 2. Unchanged tramadol and a total of 23 metabolites, consisting of 11 Phase I metabolites (M1-11) and 12 conjugates (seven glucuronides, five sulphates), were profiled, characterized and tentatively identified in urine on the basis of API ionspray-MS and MS/MS data. 3. Of the metabolites, five (M1-5) had been previously identified. 4. The metabolites were formed via the following six metabolic pathways: (1) O-demethylation, (2) N-demethylation, (3) cyclohexyl oxidation, (4) oxidative N-dealkylation, (5) dehydration and (6) conjugation. 5. Pathways 1-3 appear to be major routes, forming seven O-desmethyl/N-desmethyl and hydroxycyclohexyl metabolites. 6. Pathways 1-3 in conjunction with pathway 6 produced seven glucuronides along with five sulphates. 7. In addition, the in vitro metabolism of tramadol was conducted using a human liver microsomal fraction in the presence of an NADPH-generating system. Unchanged tramadol (82% of the sample) plus eight metabolites (M1, M2, M4-6, tramadol-N-oxide (M31), OH-cyclohexyl-M1 (M32) and dehydrated tramadol-N-oxide), were profiled and tentatively identified on the basis of MS and MS/MS data.

Ustekinumab, a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds with high affinity to human interleukin-12 and interleukin-23, has demonstrated efficacy in patients with psoriasis. The objective of this study was to perform exposure-response modeling to increase the understanding of reduction in disease severity following treatment with ustekinumab in patients with moderate to severe psoriasis who participate in two phase III studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg (n = 1312; 11,624 Psoriasis Area and Severity Index [PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was assessed using PASI scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model. None of the covariate factors evaluated (eg, demographics, baseline disease characteristics, comorbidities) significantly contributed to the between-subject variability in the pharmacodynamic parameters. The developed exposure-response model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate to severe plaque psoriasis. A robust exposure-response relationship has been confirmed for ustekinumab in psoriasis.

The new H1-receptor antagonist BW 825C and triprolidine (2.5 and 5 mg) were administered to 12 healthy male volunteers in a double blind placebo controlled, balanced, crossover design. Histamine antagonism was measured by assessment of flare and weal areas after intradermal injection of histamine. The 2 compounds were approximately equipotent in blocking the flare and weal response to intradermal histamine and had a similar duration of action. Triprolidine impaired performance of vigilance and reaction time (p less than 0.05) compared with placebo while BW 825C did not. Drowsiness measured using visual analogue scales followed both triprolidine treatments, but not BW 825C. BW 825C had a plasma half-life (t1/2) of 1.7 +/- 0.2 h and triprolidine of 4.6 +/- 4.3 h. The peak plasma level of BW 825C was approximately 6 times that of triprolidine. It was concluded that BW 825C might be a clinically active H1-antagonist with reduced sedative side-effects.

In mice and rats, there appears to be preferential brain vs. plasma distribution of tramadol over M1.