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.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Tofacitinib is an oral Janus kinase inhibitor that is being investigated for several forms of juvenile idiopathic arthritis (JIA). Previous pharmacokinetic (PK) evaluations of tofacitinib in a small cohort (N = 26) of children with polyarticular course JIA supported body weight‐based dosing in phase III studies.
WHAT QUESTION DID THIS STUDY ADDRESS?
This analysis assessed whether efficacious exposure levels are achieved across body weight categories in the proposed weight‐based tofacitinib dosing regimen.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Population PK characterization identified body weight as the only significant predictor of tofacitinib exposure and demonstrated consistent exposure in patients with JIA based on body weight‐based dosing. Both area under the plasma concentration‐time profile from time zero extrapolated to infinite time and maximum concentration were equivalent between the oral solution and tablet forms of tofacitinib.
HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?
Our findings support the development of a simplified dosing regimen of tofacitinib in patients with JIA which is more convenient to follow versus the dosing regimen used in clinical trials, and may lead to improved treatment compliance.
INTRODUCTION
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by arthritis of unknown origin that presents in patients aged less than or equal to 16 years and persists for more than 6 weeks after other conditions have been excluded. 1 , 2 , 3 , 4 Per current American College of Rheumatology (ACR) guidelines, 5 , 6 , 7 treatment for JIA depends on disease severity, clinical features, and the presence of prognostic factors. For example, in children and adolescents with the most severe forms of JIA, namely polyarticular course (pc)JIA and systemic (s)JIA, treatment with conventional synthetic and biologic disease‐modifying antirheumatic drugs (DMARDs) is recommended. However, despite advances in treatment options for JIA, a large proportion of patients have an inadequate response to DMARDs, 8 , 9 emphasizing a need for alternative therapeutic options.
Tofacitinib is an oral Janus kinase (JAK) inhibitor that is being investigated for several forms of JIA, and was first approved by the US Food and Drug Administration (FDA) in September 2020 for patients with pcJIA. 10 Tofacitinib can be administered as a tablet, or as a grape‐flavored liquid formulation for age‐appropriate use. The pharmacokinetics (PKs) of tofacitinib were previously evaluated in 26 pediatric patients with JIA in a phase I, non‐randomized, open‐label, multiple‐dose study, 11 in which PK parameters were derived using noncompartmental analysis. Oral clearance (CL/F) and apparent volume of distribution (V/F) of tofacitinib were observed to reduce with decreasing body weight, warranting dose adjustment at lower body weights. Population PK analysis performed using data from the phase I PK study was used to derive body weight‐based dosing regimens (5 mg twice daily [b.i.d.] or body weight‐based lower doses administered b.i.d. in patients weighing <40 kg) for use in the phase III study investigating the efficacy and safety of tofacitinib in pediatric patients with JIA.
More recently, a phase III, randomized, double‐blind, placebo‐controlled withdrawal study demonstrated the efficacy and safety of tofacitinib in patients with pcJIA, and also in those with juvenile psoriatic arthritis (jPsA) or enthesitis‐related arthritis (ERA), in an exploratory analysis. 12 This clinical trial met its primary end point in that JIA flare was significantly lower with tofacitinib versus placebo in patients with pcJIA. Improvements were also seen with tofacitinib versus placebo in secondary end points, including JIA/ACR response and JIA/ACR inactive disease rates, Juvenile Arthritis Disease Activity Score in 27 joints based on C‐reactive protein, and change in Childhood Health Assessment Questionnaire‐Disability Index. There were no new safety risks identified for tofacitinib in children and adolescents.
Pediatric patients with JIA who completed a phase I or phase III study, or discontinued for reasons excluding treatment‐related serious adverse events (AEs), were eligible to participate in a long‐term extension (LTE) study designed to evaluate the long‐term safety, tolerability, and efficacy of tofacitinib in patients with pcJIA, jPsA, or ERA. In an interim analysis (data cutoff June 4, 2019) of data from the LTE study, no new safety findings were reported over 66 months (5.5 years), whereas clinical efficacy was maintained over 18 months. 13
Using pooled data from these phase I, phase III, and LTE studies, the analyses reported here evaluated tofacitinib PK in children and adolescents with JIA to confirm that target efficacious exposure is achieved across body weight categories in the proposed weight‐based dosing regimen, identify potential covariates accounting for variability in exposure, assess the formulation effect of oral solution versus tablet, and further optimize the weight‐based dosing regimen. The formulation effect identified in the population PK analysis was subsequently confirmed by a clinical relative bioavailability study conducted in healthy participants.
METHODS
Population PK modeling
Study design
This was a pooled analysis of data from three studies of tofacitinib in children and adolescents with JIA, the details of which have been published previously. 11 , 12 , 13 The first was a phase I, non‐randomized, open‐label study (NCT01513902) of tofacitinib in pediatric patients aged greater than or equal to 2 years with pcJIA (defined as either extended oligoarthritis, rheumatoid factor [RF]‐positive or RF‐negative polyarthritis, jPsA, or ERA). 11 The second was a phase III, randomized, double‐blind, placebo‐controlled, withdrawal study (NCT02592434) of tofacitinib in patients aged 2–17 years with pcJIA (defined as either extended oligoarthritis, RF‐positive or RF‐negative polyarthritis, or sJIA without active systemic features), or jPsA, or ERA. 12 The third was an ongoing, open‐label LTE study (NCT01500551; PK data cutoff May 21, 2019) of tofacitinib in patients with pcJIA (defined as either extended oligoarthritis, RF‐positive or RF‐negative polyarthritis), sJIA without active systemic features, jPsA, or ERA, who had previously completed the phase I or phase III index studies, or discontinued for reasons excluding treatment‐related serious AEs. 13
The tofacitinib dosing regimen across the three studies is shown in Table S1. In summary, tofacitinib was dosed at 5 mg b.i.d., or at lower body weight‐based doses b.i.d., to achieve average concentration (C avg) comparable with those in patients who received 5 mg b.i.d. The dosing regimen in the phase III and LTE studies was selected based on the phase I findings, 12 and was predicted to achieve C avg values at steady‐state equivalent to those from efficacious doses in adults with rheumatoid arthritis (RA). All tofacitinib doses were administered as oral solution (1 mg/mL suspension), except for 5 mg b.i.d. doses, which were administered as tablets in patients weighing greater than or equal to 40 kg who were able to swallow them.
In all three studies, body weight was measured at the screening visit. In the phase III study, it was also captured on days 1, 14, 28, 56 (or 84), and 126, and then every 28 days through day 308. In the LTE study, it was measured every 3 months through month 36. If a patient terminated the phase III or LTE study early, body weight was captured at the time of termination. Across studies, if a body weight measurement was missing, the last recorded body weight was used in the relevant PK analysis.
In the phase I study, concomitant non‐steroidal anti‐inflammatory drugs (NSAIDs), methotrexate (MTX; ≤20 mg/week or 15 mg/m2/week, whichever was lower), and glucocorticoids (≤0.15 mg/kg/day of prednisone equivalent) were permitted. In the phase III and LTE studies, concomitant NSAIDs, MTX (≤25 mg/week or ≤20 mg/m2/week, whichever was lower), and glucocorticoids (≤0.2 mg/kg/day or ≤10 mg/day of prednisone equivalent, whichever was lower) were permitted.
PK sampling
To characterize the PKs of tofacitinib in plasma following multiple oral doses, a sparse PK sampling scheme was applied (Table 1). The PK sampling timepoints in the phase III and LTE studies were derived from an optimal sampling design based on the results from the phase I study. Across all timepoints, blood samples (1.0–1.2 mL) were collected in lithium heparin tubes. Plasma was extracted via centrifugation at ~1700 g for 10 min at 4°C and stored at ~−20°C within 1 h of collection.
TABLE 1.
PK sampling scheme.
| Phase I study a | Phase III study b | LTE study c |
|---|---|---|
| All patients: 0 (predose), 0.5, 1, 4, and 8 h post‐morning dose on day 5 | First 40 patients enrolled: d 0.25, 0.75, and 3 h postdose on day 1 | All patients: 0 (predose), 0.5, and 2 h postdose at months 12, 24, and 36 visits, and/or at early termination (if feasible up to month 36) |
| All subsequent patients enrolled: d 0 (predose), 0.75, and 3 h postdose on day 14 (or day 28) | ||
| All patients: 0 (predose) and 0.75 h postdose on day 84 (or later visit up to day 126) |
Abbreviations: JIA, juvenile idiopathic arthritis; LTE, long‐term extension; PK, pharmacokinetic.
NCT01500551 (PK data cut‐off May 21, 2019).
Excluding patients with systemic JIA without active systemic features, for whom the first PK sampling time was 0 (predose), 0.75, and 3 h postdose on day 14 (or day 28).
The samples were analyzed at WuXi AppTec, Shanghai, China, and PPD, Middleton, WI, USA, using a validated analytical method in compliance with sponsor‐standard operating procedures. Tofacitinib samples were assayed using a validated, sensitive, and specific high‐performance liquid chromatography–tandem mass spectrometry method. The lower limit of quantification for tofacitinib was 0.100 ng/mL. All PK observations without recorded sampling or measuring times, or those not associated with a dosing event (≥30 h postdose), were regarded as nonevaluable. No data imputations were performed.
PK modeling
The PK analysis population was defined as all patients who were enrolled and treated, with at least one measurable PK sample. A nonlinear mixed‐effects modeling approach was used for the population PK model, and the population parameter variability was assumed to be log‐normally distributed for PK parameters. Analyses were performed using NONMEM 7.4.1 (ICON Development Solutions), with Perl‐speaks‐NONMEM 4.8.0 as supporting software (model code provided in Supplementary Materials S1). 14 , 15
Based on mechanistic, physiological, and clinical plausibility, potential parameter‐covariate combinations were explored and considered for inclusion in the PK model (Table S2). The prespecified covariates, relating to patient demographics, disease characteristics, clinical laboratory parameters, concomitant medications, and formulations, were selected using a stepwise‐covariate modeling approach. The parameter‐covariate relationship was evaluated using stepwise forward‐inclusion (p < 0.05) backward‐deletion (p < 0.001) procedures for the PK parameters, CL/F, V/F, first‐order absorption rate constant (k a ), and bioavailability. A sampling importance re‐sampling (SIR) procedure was implemented in Perl‐speaks‐NONMEM 4.8.0 to construct 95% confidence interval (CI) for the parameter estimates. 16 , 17
The effect of time‐varying body weight on CL/F and V/F was characterized using an allometric model with estimated exponent. The exponents (i.e., power coefficients) were estimated using the median body weight of 46.3 kg. Four additional weight descriptors were also evaluated to account for the presence of patients meeting the Centers for Disease Control (CDC) and Prevention criteria for “obesity” 18 : fat‐free mass, 19 lean body mass, 20 ideal body mass, 21 and normal fat mass. 22 Assessment of formulation effect was tested as a fractional increase of the reference formulation (tablet) by the test formulation (oral solution) on the absorption rate or bioavailability.
Visual predictive checks (VPC) and goodness of fit (GOF) plots were generated to validate and assess adequacy of the final model. VPC plots over time after dose, and across baseline body weight and patient age, were examined. The quality of the final model predictions was determined by the agreement between the intervals of the simulated percentiles and estimated percentiles of the observed data.
To evaluate the effectiveness of the weight‐based dosing regimen, model‐estimated C avg for each individual patient in the phase III study was plotted against four body weight groups (10 to <15, 15 to <25, 25 to <40, and ≥40 kg).
Development of a simplified dosing regimen for clinical use in patients with JIA
Simulations were performed to support a simpler weight‐based dosing regimen, with fewer weight categories than used in the phase III study, for clinical use of tofacitinib in pediatric patients with JIA. Prediction of exposure metrics for typical patients was assessed at different tofacitinib doses for different body weights to match the targeted coverage from the tofacitinib 5 mg b.i.d. dosing group in pediatric patients with JIA. The distribution of body weight versus age in a healthy population (aged 2–20 years) was obtained from the CDC and Prevention database. 23 , 24 Body weight was then adjusted for the JIA population based on a Z‐score method, widely used in anthropometry to quantify a measurement's distance from the mean. The aim of the body weight adjustment was to derive the fifth percentile body weight of a 2‐year‐old patient with JIA, based on Z‐scores observed clinically in the 2–6‐year‐old weight group. This value was set as the lower boundary of the weight range for dosing simulation. Variations of the weight‐based dosing regimen were simulated based on the final PK model to evaluate the potential for further simplification. Because C avg was expected to be the driver of tofacitinib efficacy, 25 the proposed weight‐based dosing scheme was designed to ensure similar C avg values across body weight ranges. C avg values within the body weight groups were calculated, and compared with the median and range of C avg values from the tofacitinib 5 mg b.i.d. dosing scheme in pediatric patients with JIA. In addition, C avg values were compared with predicted median C avg values for tofacitinib 3 and 5 mg b.i.d. in adult patients with RA. Maximum concentration (C max) values within the JIA patient body weight groups were also calculated and compared with the median of the C max values for tofacitinib 5 and 10 mg b.i.d. in adult patients with RA. To further quantify the potential difference between the simplified dosing regimen and the dosing regimen previously used in clinical studies, the estimated tofacitinib C avg, C max, and minimum concentration (C min) between the two dosing regimens were compared.
Relative bioavailability study
A phase I, randomized, open‐label, two‐period, two‐sequence, crossover, single‐dose study to evaluate the relative bioavailability and safety of tofacitinib 5 mL oral solution (1 mg/mL) and 5 mg tablet was conducted at a single research center in the United States in healthy adult participants. Key inclusion and exclusion criteria are described in the Supplementary Materials S1. Briefly, eligible participants were 18–55 years of age and healthy, had a body mass index (BMI) of 17.5–30.5 kg/m2 and a total body weight of greater than 50 kg, and had no evidence of Mycobacterium tuberculosis.
Eligible participants were randomized 1:1 to one of two treatment sequences, receiving either the test treatment (single dose of 5 mL tofacitinib oral solution [1 mg/mL]) at period 1 and the reference treatment (single dose of 5 mg tofacitinib tablet [immediate‐release formulation]) at period 2, or the reference treatment at period 1 and the test treatment at period 2 (Table S3). There was a washout interval of at least 48 h between study periods. For both oral solution and tablet formulations, patients received tofacitinib following an overnight fast of greater than or equal to 10 h. Tofacitinib was administered by site personnel with ~240 mL of ambient temperature water. The tablet formulation was to be swallowed whole with no manipulation or chewing prior to swallowing.
The primary objective was to demonstrate the equivalence of the extent of exposure between a single dose of tofacitinib 5 mL oral solution (1 mg/mL) relative to the 5 mg tablet. Secondary objectives included the evaluation of the C max difference between the single‐dose tofacitinib 5 mL oral solution and 5 mg tablet, and the safety and tolerability of tofacitinib following single‐dose administration of the oral solution or tablet. The primary end points were the area under the plasma concentration‐time profile from time zero extrapolated to infinite time (AUCinf) and AUC profile from time zero to the time of the last quantifiable concentration (AUClast). Secondary end points included C max and reported AEs. PK blood samples were collected at predose and 0.25, 0.5, 1, 2, 3, 4, 8, 12, 16, and 24 h following treatment administration.
Approximately 12 healthy male and female (non‐childbearing potential) participants were planned to be enrolled in the study (6 in each treatment sequence). “Healthy” was determined by medical evaluation including medical history, physical examination, laboratory tests, blood pressure, pulse rate, oral temperature, and 12‐lead electrocardiogram. A sample size of 12 participants (6 per sequence) was determined to provide greater than or equal to 99% power that the 90% CI for the ratio of test to reference treatment AUCinf will lie within the acceptance region of 80–125%.
At screening, participants were assigned a number by the investigator. Pfizer provided the investigator with a randomization schedule and the participant received the study treatment regime assigned to the corresponding randomization number.
PK parameters of tofacitinib for each participant following single‐dose oral administration were derived from the concentration‐time profiles using noncompartmental analysis (calculation details are shown in Table S4). Natural log‐transformed PK parameters (AUCinf and C max) were analyzed using a mixed‐effect model with sequence, period, and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (test – reference) and the corresponding 90% CIs were reported from the model.
Ethics approval and consent to participate
All studies were conducted in accordance with the Declaration of Helsinki and International Council on Harmonization Guidelines for Good Clinical Practice and were approved by the institutional review board and/or independent ethics committee for each study center. Written informed consent/assent was provided by parents/legal guardians/patients/participants.
RESULTS
Population PK modeling
Patients
A total of 246 patients (aged 2–17 years) with 1392 plasma concentration records were included in the PK modeling analysis. The total number of records with concentrations below the level of quantification was 65, which was less than 10% of the final total records, hence they were ignored for modeling. Demographics and baseline disease characteristics are summarized in Table 2. Overall, 74.0% of patients were female, 87.8% were White, 2.0% were Black, 10.2% were “other” races, and none were Asian. Median (range) body weight was 46.3 (11.1–121.8) kg. Patients with JIA who enrolled in these studies tended to have higher BMI versus a general population of a comparable age for both genders, although this was mostly for patients greater than 5 years (Figure S1). Of the 246 patients included in this analysis, 40 (16.3%) were in the “overweight” category, and 28 (11.4%) were in the “obese” category, according to CDC and Prevention guidelines. 18
TABLE 2.
Demographics and baseline disease characteristics of the PK analysis population.
| Demographic or baseline disease characteristic | PK analysis population a (N = 246) |
|---|---|
| Age (years), mean (range) | 11.6 (2.0–17.0) |
| Female, n (%) | 182 (74.0) |
| Body weight (kg), median (range) | 46.3 (11.1–121.8) |
| Race, n (%) | |
| White | 216 (87.8) |
| Black | 5 (2.0) |
| Other | 25 (10.2) |
| Asian | 0 (0) |
| Concomitant medications, n (%) | |
| NSAIDs | 40 (16.3) |
| Glucocorticoids | 13 (5.3) |
| MTX | 38 (15.4) |
| Number of prior DMARD failures, n (%) | |
| 0 | 17 (6.9) |
| 1 | 112 (45.5) |
| 2 | 64 (26.0) |
| 3 | 53 (21.5) |
| JIA category, n (%) | |
| Extended oligoarthritis | 31 (12.6) |
| RF+ polyarthritis | 38 (15.4) |
| RF− polyarthritis | 120 (48.8) |
| sJIA without active systemic features | 12 (4.9) |
| jPsA | 22 (8.9) |
| ERA | 23 (9.3) |
| PtGA score, mean (SD) | 6.5 (1.9) |
| CHAQ score, mean (SD) | 1.0 (0.8) |
Abbreviations: CHAQ, Childhood Health Assessment Questionnaire; DMARD, disease‐modifying antirheumatic drug; ERA, enthesitis‐related arthritis; JIA, juvenile idiopathic arthritis; jPsA, juvenile psoriatic arthritis; MTX, methotrexate; NSAID, non‐steroidal anti‐inflammatory drug; PK, pharmacokinetic; PtGA, Patient Global Assessment of Disease Activity; RF+, rheumatoid factor‐positive; RF−, rheumatoid factor‐negative; SD, standard deviation; sJIA, systemic juvenile idiopathic arthritis.
Data were pooled from one phase I (NCT01513902), one phase III (NCT02592434), and one LTE (NCT01500551; PK data cutoff May 21, 2019) study of tofacitinib in pediatric patients with JIA.
Initially, 100 patients received oral solution and 146 patients received tablets, with 11 patients switching formulations during the studies.
PK modeling
A one‐compartment model with first‐order elimination and absorption with a lag time sufficiently described the data. The covariates evaluated in the model were sex; age (time‐varying and at baseline); race; JIA category; baseline creatinine clearance, C‐reactive protein, alkaline phosphatase, aspartate transaminase, and alanine transaminase; concomitant use of oral steroids, NSAIDs or COX‐2 inhibitors, MTX, and tumor necrosis factor inhibitors; number of prior DMARD failures; and formulation. Body weight was highly correlated with height, BMI, body surface area (BSA), and age with correlation coefficients of 0.864, 0.882, 0.974, and 0.803, respectively. Because body weight is a structural covariate on CL/F and V/F, these covariates (i.e., height, BMI, and BSA) were not tested, except for age, which was recommended according to General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products FDA guidance. 26 All parameters were adequately estimated with acceptable relative standard error (<40%). Parameter uncertainty distribution estimated using SIR demonstrated relatively tight 95% CIs for all parameters. Sufficient numeric identifiability is further supported by lack of final estimated parameter correlation (≤0.8) and the model condition number being less than 1000 (i.e., 250).
The estimates (95% CI from SIR) for a reference individual with a typical body weight of 46.3 kg taking the tablet formulation were 26.05 L/h (25.20–27.13) for CL/F, 89.22 L (86.12–92.91) for V/F, 2.78 h−1 (2.29–3.44) for k a , and 0.19 h (0.17–0.20) for absorption lag time (Table 3). The estimated allometric exponents (95% CI) to describe the effect of body weight on CL/F and V/F were 0.31 (0.25–0.37) and 0.54 (0.48–0.60), respectively (Table 3). When additional weight descriptors were evaluated to account for the presence of patients meeting the CDC and Prevention criteria for “obesity,” the estimated PK parameters were comparable to those based on total body weight (data available from the corresponding author on request). Therefore, in consideration of patient convenience, the model based on total body weight was retained as the final model in informing on dosing regimen. For the reference individual, tofacitinib half‐life is expected to be 2.37 h, and the tofacitinib 5 mg b.i.d. dose is expected to result in a steady‐state 24‐h AUC of 383 ng∙h/mL. The interindividual variability (% coefficient of variation) estimates from the final model for CL/F and k a were 23.5% and 120.9%, respectively. The only significant covariate identified was formulation on k a , where the oral solution was associated with faster absorption versus the tablet formulation (ka ratio of 1.64 [0.95–2.68]; Table 3), resulting in 113.9% (95% CI: 108.0–120.7%) higher C max with solution versus tablet for a typical patient with JIA with a body weight of 46.3 kg. Because formulation was not a significant covariate on other PK parameters, the C avg between the oral solution and tablet was expected to be comparable.
TABLE 3.
Parameter estimates for the final model.
| Parameter | Estimate | RSE (%) | SIR (95% CI) |
|---|---|---|---|
| CL/F (L/h) | 26.05 | 2.30 | 25.20–27.13 |
| V/F (L) | 89.22 | 2.55 | 86.12–92.91 |
| k a (h−1) | 2.78 | 12.04 | 2.29–3.44 |
| Exponent on CL/F | 0.31 | 13.40 | 0.25–0.37 |
| Exponent on V/F | 0.54 | 9.57 | 0.48–0.60 |
| Covariance between CL/F and V/F | 0.27 | 38.91 | 0.14–0.41 |
| Residual error (%) | 40.98 | 5.95 | 37.84–44.46 |
| Lag time (h) | 0.19 | 5.02 | 0.17–0.20 |
| Residual error before TAD = 1.08 h (%) | 67.96 | 6.17 | 62.99–73.44 |
| Formulation effect | 1.64 | 38.37 | 0.95–2.68 |
| IIVCL/F | 0.06 | 18.27 | 0.04–0.07 |
| IIVCL/F‐ka a | −0.10 | −33.97 | −0.15 to −0.05 |
| IIVka | 1.46 | 16.31 | 1.13–1.90 |
| IIVCL/F‐residual error a | 0.07 | 24.09 | 0.05–0.10 |
| IIVka‐residual error a | −0.57 | −11.47 | −0.68 to −0.44 |
| IIVresidual error | 0.25 | 13.61 | 0.20–0.31 |
Note: η‐shrinkages were generally low (<20%).
Abbreviations: CI, confidence interval; CL/F, oral clearance; h, hour; IIV, interindividual variability; k a , first‐order absorption rate constant; RSE, relative standard error; SIR, sampling importance re‐sampling; TAD, time after dose; V/F, apparent volume of distribution.
Represents the off‐diagonal elements of the omega block.
VPC suggests that the model adequately described the observed data over time, and across body weights and ages (Figure 1). GOF plots demonstrated that the model appropriately described the observed tofacitinib concentration data (Figure S2).
FIGURE 1.
Prediction‐corrected visual predictive check for final PK model (a) over time after dose; and across (b) baseline body weight; and (c) baseline age. Red dashed lines represent 90% CI (95% upper limit and 5% lower limit) of observed data. Red solid line represents median (50%) of observed data. Black dashed lines represent 90% predictive interval (95% upper limit and 5% lower limit) based on simulations. Black solid line represents median based on simulations. Shaded area represents predicted 95% CI of upper limit, lower limit, or median (50%) based on simulation. CI, confidence interval; PK, pharmacokinetic.
The current dosing regimen provided consistent tofacitinib exposure in patients across all body weight groups, with comparable median C avg values across the groups, and a less than three‐fold difference across all individual C avg values (Figure 2).
FIGURE 2.
Estimated individual C avg for pediatric patients with JIA in the phase III study. aNCT02592434. C avg, average concentration; JIA, juvenile idiopathic arthritis.
Recommendations for a simplified dosing regimen for clinical use in pediatric patients with JIA
With Z‐score adjustment of the data from the CDC growth charts, the 5th percentiles of weight distribution for 2‐year‐old male and female patients were calculated as 9.6 kg and 10.2 kg, respectively. Assuming a 1:1 ratio, the average of both values (9.9 kg; rounded to 10 kg) was used as the lower weight boundary for dosing simulation. Given the PK characterization and variability in pediatric patients with JIA, a simplified dosing regimen was proposed: 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 or solution in patients greater than or equal to 40 kg. The outcome of the proposed dosing regimen, in terms of C avg distributions within each tofacitinib dose group for body weight‐based 5 mg b.i.d. dose equivalent scenarios, is shown in Figure 3a. With this simplified dosing regimen, consistent C avg values were predicted across all body weight groups. In the tofacitinib 5 mg b.i.d. dosing group, C avg values predicted for the tablet formulation were comparable with those predicted for the oral solution. In addition, the comparison of the estimated PK parameters (i.e., C avg, C max, and C min) between the simplified dosing regimen and the dosing regimen used in the clinical studies clearly demonstrated comparable exposure between the two dosing regimens, where the ratio of PK parameters across all weight subgroups between the two dosing regimens were less than or equal to 1.15 (Table S5).
FIGURE 3.
Predicted steady‐state (a) C avg and (b) C max with proposed dosing regimen (5 mg b.i.d. equivalent) in increasing body weight groups in adult patients with RA. The dashed horizontal lines represent the predicted median values from the adult RA population PK model. b.i.d., twice daily; C avg, average concentration; C max, maximum concentration; PK, pharmacokinetic; RA, rheumatoid arthritis.
To maintain consistent C avg in pediatric patients with JIA, C max was predicted to increase with decreasing body weight (Figure 3b). Based on the proposed dosing regimen, the highest C max was expected in patients with the lowest body weight, which was comparable with C max values for tofacitinib 5 mg b.i.d. in adult patients with RA. A slightly higher C max (<20%) was predicted when tofacitinib 5 mg b.i.d. was administered as an oral solution versus tablet formulation, due to the faster absorption rate associated with oral solution versus tablet.
Relative bioavailability study
Patients were enrolled between October 11, 2019, and December 12, 2019. A total of 12 participants were assigned to study treatment, with 11 participants receiving both treatments. One participant discontinued following completion of study period 1 due to a family emergency. All 12 participants were included in the PK and safety analyses.
Baseline characteristics are summarized in Table S6. All participants were men, and the majority (66.7%) were Black/African American. The mean age was 38.3 years (range: 25–53 years). The mean weight and BMI were 89.3 kg (range: 71.4–115.4 kg) and 27.0 kg/m2 (range: 22.4–29.6 kg/m2), respectively.
A summary of the plasma tofacitinib PK parameters is shown in Table 4. Following administration of single oral doses of tofacitinib, median time to C max was comparable between oral solution and tablet (0.5 and 1.0 h, respectively). Mean elimination half‐life values were nearly identical (~3 h) for both formulations. The adjusted geometric mean ratios (90% CI) of the AUCinf and C max between the oral solution and the tablet were 1.04 (1.00–1.09) and 1.10 (1.00–1.21), respectively, demonstrating the bioequivalence of the two formulations.
TABLE 4.
Summary of plasma tofacitinib PK parameters.
| Tofacitinib 5 mg tablet (n = 11) | Tofacitinib 5 mg oral solution (n = 12)p | Ratio a of adjusted geometric means (90% CI) | |
|---|---|---|---|
| AUCinf (ng∙h/mL) b | 126.8 | 132.4 | 1.04 (1.00–1.09) |
| AUClast (ng∙h/mL) b | 125.7 | 131.3 | 1.04 (1.00–1.09) |
| C max (ng/mL) b | 34.6 | 38.0 | 1.10 (1.00–1.21) |
| T max (h), median (range) | 1 (0.5–1.0) | 0.5 (0.5–1.0) | – |
| t 1/2 (h), mean (SD) | 3.3 (0.5) | 3.3 (0.4) | – |
Abbreviations: AUCinf, area under the plasma concentration‐time profile from time zero extrapolated to infinite time; AUClast, AUC‐time profile from time zero to the time of the last quantifiable concentration; CI, confidence interval; C max, maximum concentration; h, hour; n, number of participants in the treatment group; PK, pharmacokinetic; SD, standard deviation; t 1/2, half‐life; T max, time to C max.
Test/reference.
Adjusted geometric means.
A summary of the treatment‐emergent AEs (TEAEs) is provided in Table S7. There were no deaths, serious or severe AEs, discontinuations due to AEs, dose reductions, or temporary discontinuations due to AEs that were treatment‐related. There were no TEAEs reported during treatment with the tofacitinib 5 mg tablet. Six all‐causality TEAEs were reported in four participants during treatment with tofacitinib 5 mL oral solution but none were considered to be treatment‐related by the investigator.
DISCUSSION
This pooled analysis of data from phase I, phase III, and LTE studies described tofacitinib PKs in children and adolescents with JIA to evaluate potential covariates accounting for variability in tofacitinib exposure, assess the formulation effect of oral solution versus tablet, and confirm whether efficacious exposure levels were achieved across weight categories in the current weight‐based dosing regimen. Together, these findings were then used to inform dosing regimen recommendations for children and adolescents with JIA.
The findings of this pooled analysis demonstrate that tofacitinib population PKs in children and adolescents with JIA were adequately described by a one‐compartment model parameterized in terms of CL/F, V/F, and first‐order absorption with a lag time. Although drug absorption with the oral solution was slightly faster (1.64‐fold) than with the tablet formulation, this was not expected to result in clinically meaningful differences in the PKs of the oral solution versus tablet. This model‐based finding was confirmed by a subsequent relative bioavailability study in healthy adult participants where both AUCinf and C max were shown to be equivalent between the oral solution and tablet. This validation of the population PK model‐based finding demonstrates the usefulness of the modeling technique in generating valuable insight from sparse PK samples in patients. Furthermore, results of the covariate analysis demonstrated that tofacitinib does not require dose modification or restrictions for any covariates, except body weight, to account for differences in C avg.
Tofacitinib CL/F in children and adolescents with JIA with a typical body weight of 46.3 kg (26.05 L/h) is within the range that has been observed in adults with RA (18.4 L/h), 27 plaque psoriasis (26.7 L/h), 28 psoriatic arthritis (20.4 L/h), 29 and ulcerative colitis (26.3 L/h). 30 This is consistent with the recent report where comparable drug exposures were observed between patients with RA and polyarticular JIA for multiple biologics. 31 Additionally, robust efficacy was demonstrated in both pcJIA and RA after treatment with tofacitinib 5 mg b.i.d., 12 , 25 , 32 suggesting efficacy extrapolation between the two populations for an oral JAK inhibitor, as has been demonstrated recently for four biologics. 31
The estimated allometric exponent for the effect of body weight on CL/F (0.31) is lower than the typically anticipated 0.75 33 or 0.67. 34 , 35 The biological reason for this lower allometric exponent for tofacitinib in patients with JIA is not clear. Of note, the estimated allometric exponent is still within the range that has been reported previously (0.29–1.2). 36 The current dataset contains PK information from more than 200 pediatric patients with body weights ranging from 11.1 to 121.8 kg, with 11.4% of patients considered “obese” per CDC and Prevention criteria. When four additional weight descriptors (fat‐free mass, lean body mass, ideal body mass, and normal fat mass) were evaluated to account for the presence of “obese” patients, the estimated PK parameters were comparable to those based on total body weight. Additionally, there is less concern of confounding by enzyme ontogeny because all patients are aged greater than or equal to 2 years. Furthermore, the current study design should have provided sufficient power to estimate the allometric exponent accurately, per previously reported criteria. 37
Overall, our findings support the development of a simplified dosing regimen, compared with that used in the phase III study, for clinician and patient convenience during clinical use of tofacitinib. A revised regimen was proposed, in which patients are allocated to one of just three body weight‐based dosing groups. Under this simplified dosing regimen, consistent C avg values were still expected across all body weight‐based dosing groups. In the tofacitinib 5 mg b.i.d. dosing group, comparable C avg values were expected with the oral solution and tablet, whereas a slightly higher C max was expected with the oral solution versus tablet formulation, as indicated by a 1.64‐fold higher absorption rate constant for the solution compared with the tablet formulation. The highest C max was predicted in patients with the lowest body weight. This is due to the established PK allometry in pediatric patients with JIA: whereas CL/F and V/F decrease with decreasing body weight, they do so with different exponents (0.31 and 0.54, respectively). Additionally, those patients with the lowest body weight were receiving the oral solution, which was associated with a higher C max than the tablet. Because half‐life is determined by the ratio of V/F over CL/F, it therefore also decreases with decreasing body weight. Although the estimated exponents for CL/F and V/F are substantially lower than literature‐reported exponents of 0.75 and 1, respectively, 38 , 39 , 40 tofacitinib C max, as well as C avg values, changed in patients with JIA based on the interplay between respective body weight and CL/F and V/F. However, the highest C max, observed in the lowest body weight group, remained comparable to that observed with tofacitinib 5 mg b.i.d. in adults with RA.
Notably, the recommended tofacitinib doses for the treatment of pcJIA follow the proposed simplified dosing regimen. 10 With just three body weight groups to be considered, this simplified dosing regimen is more convenient for patients/their caregivers to follow versus the current dosing regimen used in the phase I, phase III, and LTE studies, as fewer treatment modifications will be required due to changes/fluctuations in weight. In turn, this may lead to improved treatment compliance.
Some limitations remain associated with the PK modeling analyses. First, the sparse PK sampling scheme and the relatively small sample size of pediatric patients with JIA may have limited the ability to detect all covariates. Second, this analysis did not include any patients with sJIA with active systemic features. Tofacitinib PKs in this patient group will be assessed in an ongoing phase III study (ClinicalTrials.gov: NCT03000439). The randomized phase I clinical trial in healthy participants also had a small sample size and all participants were men and from the United States, which may limit the generalizability of these observations.
In conclusion, the PK findings from this pooled analysis of phase I, phase III, and LTE data suggest that a simplified tofacitinib dosing regimen could be implemented in children and adolescents with JIA. This proposed body weight‐based dosing regimen could inform treatment guidelines for children and adolescents with JIA.
AUTHOR CONTRIBUTIONS
C.C., A.H., A.D., and A.M. designed the research. C.V. and C.C. performed the research. C.C., C.V., X.W., T.N., A.M., and A.D. analyzed the data. All authors wrote the manuscript.
FUNDING INFORMATION
This study was sponsored by Pfizer. Pfizer authors participated in the study design, analysis and interpretation of the data, and the writing of the manuscript.
CONFLICT OF INTEREST STATEMENT
C.C., X.W., A.D., T.N., and A.M. are employees and shareholders of Pfizer Inc. C.V. and A.H. were employees and shareholders of Pfizer Inc. at the time of the analysis.
Supporting information
Data S1
ACKNOWLEDGMENTS
The authors thank the study patients and investigators. Medical writing support, under the direction of the authors, was provided by Kirsten Woollcott, MSc, and Robert Morgan, PhD, CMC Connect, a division of IPG Health Medical Communications, and was funded by Pfizer, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med. 2022;175:1298‐1304).
Chang C, Vong C, Wang X, et al. Tofacitinib pharmacokinetics in children and adolescents with juvenile idiopathic arthritis. CPT Pharmacometrics Syst Pharmacol. 2024;13:599‐611. doi: 10.1002/psp4.13104
Cheng Chang and Camille Vong shared first author.
Trial registration: NCT01513902, NCT02592434, NCT01500551, and NCT04111614.
DATA AVAILABILITY STATEMENT
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.