Dupilumab pharmacokinetics in Chinese healthy subjects and patients with atopic dermatitis: Results of two randomized, double-blind, placebo-controlled studies.
Dupilumab, a fully human monoclonal antibody targeting IL-4Rα, has demonstrated rapid and sustained improvements in clinical outcomes in patients with atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps.
In a phase 1, double-blind, ascending-dose study, 30 healthy Chinese adults were randomized to single subcutaneous doses of dupilumab 200, 300, 600 mg, or placebo. In a phase 3, double-blind study, 165 Chinese adults with AD were randomized to dupilumab 300 mg or placebo every 2 weeks.
Following single doses of dupilumab 200, 300, and 600 mg in the phase 1 study, mean serum maximum concentrations (Cmax) were 25.4 ± 4.0, 37.2 ± 14.5, and 77.3 ± 19.0 mg/L, respectively. For a 1.5-fold increase in dupilumab dose, 1.31-, 1.73-, and 1.66-fold increases in Cmax, area under the curve to real time (AUClast), and extrapolated to infinity (AUC) were observed, respectively, while a 2-fold dose increase resulted in 2.17-, 2.81-, and 2.80-fold increases, respectively. In the phase 3 study, mean dupilumab trough concentrations were 78.8 ± 32.0 and 86.4 ± 33.6 mg/L at weeks 12 and 16, respectively.
Cmax increased approximately proportionally to dose, while AUC and AUClast increased greater than proportionally. Dupilumab pharmacokinetics were generally comparable between Chinese and non-Asian healthy subjects (single dose) and between Chinese and non-Asian AD patients (repeated doses), with differences accounted for by body weight. As differences in exposure by weight are unlikely to be clinically relevant based on late-stage study results, no dose adjustment by ethnic origin or weight is required.
Clot PF
，Kamal M
，Sun J
，Xu C
，Kong F
，Gu Y
，Yang N
，Yin W
，Chen B
，Ming JE
，Yuan Y
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Pharmacokinetics of Risankizumab in Asian Healthy Subjects and Patients With Moderate to Severe Plaque Psoriasis, Generalized Pustular Psoriasis, and Erythrodermic Psoriasis.
Risankizumab, a humanized monoclonal antibody that targets interleukin-23 p19 subunit, was developed for the treatment of psoriasis. This work characterizes risankizumab pharmacokinetics in Japanese and Chinese healthy subjects compared with white healthy subjects and in Japanese patients with moderate to severe plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis. A phase 1, single-dose study evaluated risankizumab pharmacokinetics and safety/tolerability in healthy white (18 and 300 mg subcutaneous [SC]), Japanese (18, 90, and 300 mg SC and 200, 600, and 1200 mg intravenous [IV]), and Chinese (18, 90, and 300 mg SC) subjects; pharmacokinetic data were analyzed using noncompartmental methods. Risankizumab pharmacokinetic data from phase 2/3 studies in Japanese patients with plaque psoriasis, generalized pustular psoriasis, or erythrodermic psoriasis following multiple SC doses of 75 mg or 150 mg were analyzed using a population pharmacokinetic approach along with data from the phase 1 and global phase 1 to 3 studies. Risankizumab plasma exposures (peak plasma concentration and area under the concentration-time curve) were approximately dose-proportional across 18- to 300-mg SC or 200- to 1200-mg IV doses. Risankizumab terminal elimination half-life (harmonic mean 27-34 days) was comparable across doses and ethnicities. Risankizumab exposures were approximately 20% to 30% higher in Japanese and Chinese healthy subjects compared with white healthy subjects or in Japanese patients compared with non-Japanese patients. After accounting for body-weight differences, risankizumab exposures were comparable across ethnicities. Overall, there was no ethnic impact on risankizumab pharmacokinetics, and the small difference in exposure due to body weight has no clinical relevance.
Khatri A
，Eckert D
，Oberoi R
，Suleiman A
，Pang Y
，Cheng L
，Othman AA
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Differential pharmacokinetics of diclofenac potassium for oral solution vs immediate-release tablets from a randomized trial: effect of fed and fasting conditions.
To compare the pharmacokinetics of, and food effect on, diclofenac potassium delivered as an oral solution vs an immediate-release tablet.
Diclofenac potassium for oral solution is the only nonsteroidal anti-inflammatory drug approved as monotherapy for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older. It is formulated with potassium bicarbonate as a buffering agent to raise the pH and consequently increase the aqueous solubility of diclofenac in the acidic environment of the stomach following oral administration. The dosage is 50 mg of powdered diclofenac potassium dissolved in 1 to 2 ounces (30 to 60 mL) of water prior to administration, with dosing time in relation to food intake not specified - this was the case for the pivotal efficacy and safety trials in subjects with acute migraine attacks in which the primary endpoints were achieved. For acute treatment of migraine attacks, rapid onset of pain relief is desirable and is likely related to a rapid appearance of an effective concentration of the drug in the systemic circulation. The rate at which an orally administered drug reaches the blood is affected by both its formulation and the presence of food in the stomach. The present study was designed to investigate the pharmacokinetics of 2 formulations of diclofenac potassium, an immediate-release tablet and an oral solution, and to ascertain the effect of food.
This was an open-label, randomized, single-center, crossover trial in healthy volunteers. Subjects were randomized using computer-generated list to 1:1:1:1 ratio. They received a single 50-mg dose of diclofenac potassium in 4 sequences (ABCD, BADC, CDBA, and DCAB) during each of the 4 treatment periods. The 4 treatments were: A, oral solution fasting; B, tablet fasting; C, oral solution fed; and D, tablet fed. There was a ≥7-day washout period between dosing. Blood samples for pharmacokinetic analysis were taken for up to 12 hours post-dose and analyzed for diclofenac concentrations. Pharmacokinetic parameters, including peak concentration (Cmax ), time to Cmax (tmax ), area under the concentration-time curve (AUC) from time 0 to last measurable concentration (AUCt ), and extrapolation to infinity (AUC∞ ) were obtained using non-compartmental analysis. Comparative assessments for Cmax and AUC were performed between the solution and tablet under fed and fasting conditions and between fed and fasting states for both formulations. Bioequivalent exposure was defined as the geometric mean ratio and its 90% confidence interval falling within 80.0-125.0% for Cmax and AUC. Adverse events (AEs) were monitored throughout the trial.
Sixty-one percent of the 36 randomized subjects were male, 91.7% were Caucasian, and the mean (standard deviation [SD]) age was 31.9 (7.6) years. Thirty-three (91.7%) subjects completed all 4 treatments.
When taken under fed conditions, the oral solution resulted in an approximately 80% faster median tmax (0.17 vs 1.25 hours, P = .00015) and a 21% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 835 ± 449, P = .00061) compared with the tablet. AUC values were similar between the 2 formulations. When taken under fasting conditions, the oral solution exhibited a 50% faster median tmax (0.25 vs 0.50 hours, P = .00035) to achieve a 77% higher Cmax (mean ± SD, ng/mL: 1620 ± 538 vs 1160 ± 452, P = .00032) compared with the tablet. AUCt and AUC∞ were similar between the 2 formulations.
When taken under fed conditions, the oral solution resulted in a similar median tmax (0.17 vs 0.25 hours, P = .185) and 64% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 1620 ± 538, P < .00001) compared with fasting conditions. In comparison, the tablets under fed conditions resulted in a statistically significantly delayed median tmax (1.25 vs 0.50, P = .00143) and ∼30% lower Cmax (mean ± SD, ng/mL: 835 ± 449 vs 1160 ± 452, P = .00377). AUC values were similar between fed and fasting conditions for both formulations. Twelve subjects (33%) experienced ≥1 treatment-emergent AE during the study. All AEs were mild and resolved without treatment; none resulted in study discontinuation. More treatment-emergent AEs were reported in subjects receiving the tablet compared with the solution formulation (20.0% vs 11.8 % in fasting and 17.1% vs 8.6% in fed conditions).
Diclofenac potassium oral solution and tablet formulations produced statistically significantly different Cmax and tmax but similar AUC under fed and fasting conditions. Fed conditions produced significantly lower Cmax for both formulations and profoundly delayed tmax for the tablet, but had no effect on tmax for the solution formulation. These data provide insights into the importance of an earlier and greater exposure to diclofenac arising from the solution formulation than the tablet, which may account for the superiority in the onset and sustained pain reduction for the solution than the tablet formulation observed in the double-blind, efficacy/safety study in migraine patients conducted in Europe.
Chen C
，Bujanover S
，Kareht S
，Rapoport AM
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ResearchGate
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