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Tofacitinib pharmacokinetics in children and adolescents with juvenile idiopathic arthritis.

ABSTRACT: These analyses characterized tofacitinib pharmacokinetics (PKs) in children and adolescents with juvenile idiopathic arthritis (JIA). Data were pooled from phase I (NCT01513902), phase III (NCT02592434), and open-label, long-term extension (NCT01500551) studies of tofacitinib tablet/solution (weight-based doses administered twice daily [b.i.d.]) in patients with JIA aged 2 to less than 18 years. Population PK modeling used a nonlinear mixed-effects approach, with covariates identified using stepwise forward-inclusion backward-deletion procedures. Simulations were performed to derive dosing recommendations for children and adolescents with JIA. Two hundred forty-six pediatric patients were included in the population PK model. A one-compartment model with first-order elimination and absorption with body weight as a covariate for oral clearance and apparent volume of distribution sufficiently described the data. Oral solution was associated with comparable average concentration (C_avg) and slightly higher (113.9%) maximum concentration (C_max) versus tablet, which was confirmed by a subsequent randomized, open-label, bioavailability study conducted in healthy adult participants (n = 12) by demonstrating adjusted geometric mean ratios (90% confidence interval) between oral solution and tablet of 1.04 (1.00-1.09) and 1.10 (1.00-1.21) for area under the curve extrapolated to infinity and C_max, respectively (NCT04111614). A dosing regimen of 3.2 mg b.i.d. solution in patients 10 to less than 20 kg, 4 mg b.i.d. solution in patients 20 to less than 40 kg, and 5 mg b.i.d. tablet/solution in patients greater than or equal to 40 kg, irrespective of age, was proposed to achieve constant C_avg across weight groups. In summary, population PK characterization informed a simplified tofacitinib dosing regimen that has been implemented in pediatric patients with JIA.

SUBMITTER: Chang C

PROVIDER: S-EPMC11015083 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Tofacitinib pharmacokinetics in children and adolescents with juvenile idiopathic arthritis.

Chang Cheng C Vong Camille C Wang Xiaoxing X Hazra Anasuya A Diehl Annette A Nicholas Timothy T Mukherjee Arnab A

CPT: pharmacometrics & systems pharmacology 20240131 4

These analyses characterized tofacitinib pharmacokinetics (PKs) in children and adolescents with juvenile idiopathic arthritis (JIA). Data were pooled from phase I (NCT01513902), phase III (NCT02592434), and open-label, long-term extension (NCT01500551) studies of tofacitinib tablet/solution (weight-based doses administered twice daily [b.i.d.]) in patients with JIA aged 2 to less than 18 years. Population PK modeling used a nonlinear mixed-effects approach, with covariates identified using step ...[more]

PMID: 38298058

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Project description:BackgroundOptimal utilization of dental caries data is crucial in epidemiological research of individuals with juvenile idiopathic arthritis (JIA). The aims were to: explore whether caries is more prevalent among children and adolescents with JIA compared to controls; examine presence of caries according to JIA group, socio-behavioral and intraoral characteristics, and the extent to which surface-specific caries varies between and within individuals; assess whether surface-specific caries varies according to JIA group and dentition; and investigate whether disease-specific clinical features of JIA are associated with presence of caries.MethodsIn this comparative cross-sectional study, calibrated dentists examined index teeth (primary 2. molars, 1. permanent molars) of 4-16-year-olds with JIA (n = 219) and matched controls (n = 224), using a detailed caries diagnosis system (including enamel caries). JIA-specific characteristics were assessed by pediatric rheumatologists and socio-behavioral information collected by questionnaires. Multilevel mixed-effect logistic regressions reporting odds ratios (OR) with 95% confidence interval (CI) were applied (caries at surface level as outcome variable). Potential confounders were adjusted for, and the effect of dependency of surface-specific caries data was estimated by calculating intra-class correlation coefficients (ICC).ResultsAt individual level, no significant difference in caries prevalence was found between individuals with JIA and controls, regardless of inclusion of enamel caries. Proportion of enamel lesions exceeded dentine lesions. JIA was not associated with presence of caries, but in both groups, low maternal educational level was associated with presence of caries (OR: 2.07, 95% CI: 1.24-3.46). Occlusal and mesial surfaces, compared to buccal surfaces, had generally higher OR according to presence of caries than distal and lingual surfaces (ICC = 0.56). Surface-specific caries in the permanent dentition differed significantly according to group affiliation. Some JIA disease-specific variables were suggested to associate with presence of caries.ConclusionsNo overall difference in caries prevalence between individuals with JIA and controls was observed, but for both groups, low maternal educational level and tooth surface associated with presence of caries. Associations between JIA disease-specific variables and presence of caries cannot be excluded. Due to predominance of enamel lesions, the potential of preventative dental strategies is considerable.

Project description:BackgroundObservational studies examining the association between oral health and juvenile idiopathic arthritis (JIA) among children and adolescents have reported inconsistent findings. The aims of this systematic review and meta-analysis were to ascertain a potential difference in oral health and oral health-related quality of life (OHRQoL) among children and adolescents with JIA and healthy peers, and to assess the association of prevalence of oral diseases/conditions, temporomandibular disorders (TMD), including temporomandibular joint (TMJ) diseases, in relation to activity and severity of JIA.MethodMedline Ovid, Embase, CINAHL, SweMed+ and Cochrane Library were searched up to 25 November 2018. All articles published in English, German and Scandinavian languages focusing on children and adolescents with JIA and without JIA in relation to oral health measures, were considered. Two authors independently evaluated observational studies for inclusion. The study quality was assessed using modified Newcastle Ottawa Scale. Meta-analysis was performed for studies focusing on dental caries as an outcome.ResultsNineteen articles met the inclusion criteria, covering a range of oral diseases/conditions and OHRQoL. Eighteen studies had cross-sectional design. No mean difference of dmft/DMFT indices (decayed/missed/filled teeth) was observed between the JIA - and healthy group. None of the oral health measures including dental erosive wear, enamel defects, dental maturation and OHRQoL, indicated better oral health among children and adolescents with JIA compared to healthy group. However, periodontal conditions and TMD were more predominant among children and adolescents with JIA compared to healthy peers.ConclusionsBased on the cross-sectional studies, periodontal diseases and TMD were found to be more frequent in children and adolescents with JIA compared to healthy peers. Furthermore, more high-quality studies with large sample size are needed before we infer any concrete conclusion regarding the association between the prevalence of oral and TMJ diseases or oral conditions in relation to activity and severity of JIA.

Project description:ObjectiveWe examine levels of candidate blood-based biomarkers (CBBs) in patients with juvenile idiopathic arthritis (JIA) treated with tofacitinib.MethodsPatients with JIA who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBBs (S100A8/9, S100A12, interleukin-18 [IL-18], serum amyloid A, resistin, vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, matrix metalloproteinase 8 [MMP8], MMP2, tissue inhibitor of metalloproteinases 1, leptin, chemokine [C-X-C motif] ligand 9, soluble IL-2 receptor, intercellular adhesion molecule 1, soluble tumor necrosis factor receptor, IL-6, IL-23, monocyte chemotactic protein 1, chemokine [C-C motif] ligand 18 [CCL18], and CCL20). Association of CBBs with JIA response to treatment from baseline to week 18 were assessed.ResultsThis study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. Thirty-five percent (50 of 143) of patients had a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement, whereas 90, 121, and 137 (63%, 85%, and 96%) achieved JIA-ACR70, 50, and 30 improvement at week 18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in Juvenile Arthritis Disease Activity Score (JADAS-27) or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with week 18 improvement in JADAS-27 and JIA-ACR90 response after adjusting for age, sex, JIA disease duration, and baseline resistin (r2 0.79, SE 0.070, P < 0.01, and odds ratio [95% confidence interval] 1.134 [1.018-1.264]). HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (P = 0.0097).ConclusionAmong the CBBs included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

Dataset Information

Tofacitinib pharmacokinetics in children and adolescents with juvenile idiopathic arthritis.

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Tofacitinib pharmacokinetics in children and adolescents with juvenile idiopathic arthritis.

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