Journal of clinical pharmacology
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Randomized Controlled Trial Multicenter Study
Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis.
The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. ⋯ CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34 hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 µM (0.55 µg/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS.
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Randomized Controlled Trial Multicenter Study
Population exposure-response model to support dosing evaluation of ixekizumab in patients with chronic plaque psoriasis.
Ixekizumab (LY2439821), a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that selectively binds and neutralizes interleukin (IL) 17A has demonstrated efficacy in the treatment of psoriasis. A population pharmacokinetics-pharmacodynamics model was developed using NONMEM 7.2 to describe the temporal relationship between ixekizumab concentrations and absolute Psoriasis Area and Severity Index (PASI) scores from a phase 2 dose-finding study in chronic plaque psoriasis. The objective was to inform dose-selection for further development. ⋯ The population pharmacokinetics of ixekizumab was characterized by a two-compartment model, while the exposure-response relationship was characterized using an indirect response model that described the pharmacological effects of ixekizumab and placebo in the form of inhibition of the formation of psoriatic skin lesions. PASI 75 responder status at the Week 12 primary endpoint was found to be a significant covariate on the concentration producing half maximal effect (EC50 ). While the results suggested patient may have different levels of sensitivity to ixekizumab, it is possible that nonresponder patients assigned to lower doses of ixekizumab may potentially become responders to ixekizumab if given doses that yield adequate exposures.
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This open-label, single-center, phase I study (NCT1487564) investigated the effect of uridine diphosphate-glucuronosyltransferase2B7 (UGT2B7*2) genetic polymorphism (H268Y) on the pharmacokinetics (PK) and safety of a single, oral, 16-mg dose of OROS® hydromorphone and its metabolite in healthy Taiwanese subjects. Plasma concentrations of hydromorphone and hydromorphone-3-glucuronide were determined in 28 subjects. ⋯ No clear trend in PK parameters and no clinically significant differences in the incidence of treatment-emergent adverse events (TEAEs) were observed among different UGT2B7 genotypes. Our study found UGT2B7 polymorphism had no apparent effect on PK of OROS® hydromorphone; hydromorphone was well tolerated in pain-free volunteers when coadministered with naltrexone.