Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets.

PURPOSE: Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. METHODS: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 mg) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done. RESULTS: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 18% vs. 14% for AUC(0-6), 17% vs. 5% for AUC(0-12) and 10% vs. 8% for AUC(0-t)). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in Tmax were found. CONCLUSIONS: Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.

Bioequivalence study of a novel orodispersible tablet of meloxicam in a porous matrix after single-dose administration in healthy volunteers.

BACKGROUND: Meloxicam is a non-steroidal anti-inflammatory drug, indicated for osteoarthritis exacerbations, rheumatoid arthritis and ankylosing spondylitis symptomatic treatment. OBJECTIVE: To compare the bioavailability of a 15 mg meloxicam orodispersible tablet (ODT) and a reference 15 mg tablet in healthy volunteers. METHODS: Two randomized, crossover, bioequivalence studies were conducted. In both studies, 28 volunteers were randomly assigned to receive test ODT and reference tablet formulations in single dose under fasting conditions in two study periods, with a 7-day (Study I) or 14-day (Study II) wash-out between administrations. Blood samples were collected at pre-specified times. Pharmacokinetic parameters were obtained by noncompartmental analysis. Bioequivalence was assumed if the 90% confidence interval of the test/reference ratio of the least-squares means for Cmax, AUC0-t and AUC0-∞were within the 80.00 -125.00% range, according to the current guidelines. RESULTS: All 28 subjects in Study I and 26 subjects in study II completed the study and were included in the analysis. The 90% confidence intervals of the geometric means ratios for the logtransformed Cmax, AUC0-t and AUC0-∞were 87 - 96%, 88 - 96% and 87 - 96% in Study I, and 99 - 105%, 98 - 104% and 108 - 120% in Study II. Test product was characterized by a slightly earlier tmax than the reference, i.e., 4.9 ± 1.1 vs. 5.8 ± 2.6 hours in Study I (p = 1.000) and 3.8 ± 2.0 vs. 4.8 ±1.6 hours in Study II (p = 0.0054). The two drugs were well tolerated. CONCLUSIONS: Test and reference formulations met the regulatory criteria for bioequivalence in the fasting healthy volunteers enrolled.

Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route.

A novel aqueous progesterone formulation was developed. Study I: Three-way cross-over, open-label study in 24 post-menopausal women. Comparison of the pharmacokinetic profiles of a single 100 mg dose of test product administered by subcutaneous (s.c.) and intramuscular (i.m.) injection and an i.m. reference oily product. Study II: Three-way cross-over open-label study of 25, 50 and 100 mg s.c. single doses of the aqueous formulation in 12 post-menopausal women. Study III: Parallel-group, observer-blinded study in 25 fertile women administered multiple s.c. 25 and 50 mg doses of the aqueous formulation once daily for 11 days. Baseline-corrected pharmacokinetic parameters were evaluated. Aqueous formulation (100 mg) was promptly absorbed, achieving progesterone peak serum levels at an earlier time than the reference (1 h vs. 7 h; p < 0.0001). Test and reference were bioequivalent in the extent of exposure: confidence intervals for AUC(0-t) geometric means ratios were within the pre-specified 80-125% limits. Pharmacokinetics was linear over the range of doses studied. Steady state was reached within 4 days of multiple dose treatment. All treatments were well tolerated. Considering the advantages given by the possibility of self-medication, the s.c. aqueous formulation could offer a convenient alternative for patients on assisted reproductive technology treatments.

Pharmacokinetics, Safety, Efficacy, and Biomarker Profiles During Nemolizumab Treatment of Atopic Dermatitis in Adolescents.

INTRODUCTION: Nemolizumab, a new monoclonal antibody that targets the receptor alpha of the neuroimmune cytokine interleukin-31 (IL-31), has shown efficacy in atopic dermatitis (AD) in adults. This study evaluated the pharmacokinetics (PK) and safety of nemolizumab in adolescents with moderate to severe AD as well as the relationship between nemolizumab concentrations and clinical efficacy and the effect of nemolizumab on protein biomarkers. METHODS: Open-label, 16-week study of nemolizumab in patients aged 12-17 years with moderate to severe AD (baseline EASI ≥ 16, IGA ≥ 3, and BSA ≥ 10%) and associated pruritus with baseline average daily peak pruritus numeric rating scale (PP-NRS) intensity of at least 4. Nemolizumab was administered subcutaneously as a loading dose of 60 mg at baseline, followed by 30 mg every 4 weeks until week 12 with background topical corticosteroids (TCS) or calcineurin inhibitors (TCI). Subsequently patients were followed for 8 weeks more. Stratum corneum (SC) and plasma samples were collected for biomarker assessments. RESULTS: Twenty patients participated, with a mean age of 14.8 ± 1.6 years. The PK of nemolizumab was described by a one-compartment model with linear elimination, a first-order absorption, and a mean half-life of 16.7 ± 4.1 days. Mean trough concentrations ranged from 2935 ± 1029 ng/mL to 3292 ± 2018 ng/mL over the 16-week treatment period. There was a marked improvement in rash, itch, and sleep with a decrease from baseline to week 16 in EASI by 66.5 ± 32.5%, in PP-NRS by 43.2 ± 37%, and in sleep disturbance numeric rating scale by 53.5 ± 47.8%. The popPK and PK/PD analyses confirmed that model-predicted exposure and efficacy of nemolizumab were similar in adolescents compared to adults receiving the same dosing regimens. Age did not impact PK parameters, while the main source of PK variability was body weight. Analyses of SC samples identified a panel of AD-related pro-inflammatory biomarkers that were upregulated in lesional skin (compared to non-lesional skin) and correspondingly downregulated in clinical responders to nemolizumab (based on EASI75 and PP-NRS ≥ 4). Four biomarkers (CCL20, CCL22, CCL27, and VEGF) had changes that were 1.9-3.5-fold higher in EASI responders than in EASI non-responders (all p < 0.05). Analysis showed no significant correlation between plasma biomarkers and clinical scores. Adverse events were experienced by 33.3% of subjects (n = 6) and were primarily mild or moderate in severity. CONCLUSIONS: Nemolizumab PK and safety profiles in adolescents with moderate to severe AD are consistent with previous nemolizumab studies in adults. PK/PD models demonstrate similar exposure-response profiles in 12- to 17-year-old adolescents and adults for three clinical endpoints (EASI, IGA, and PP-NRS). Nemolizumab treatment reversed AD-related pro-inflammatory biomarkers in skin, indicating that the neuroimmune cytokine IL-31 is an important mediator of multiple pathways in AD. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT03921411.

Pharmacokinetics and Safety of a Diclofenac Sodium 75 mg/1 mL Solution (Akis®/Dicloin®) Administered as a Single Intravenous Bolus Injection in Healthy Men and Women.

BACKGROUND: A 1-mL aqueous solution for parenteral injection containing diclofenac sodium and hydroxypropyl-ß-cyclodextrin, presently on the market for intramuscular and subcutaneous administration (Akis®/Dicloin®), was further developed for intravenous (i.v.) bolus administration. OBJECTIVES: The study objective was to compare the tolerability and diclofenac pharmacokinetics after a single i.v. bolus of the investigational solution to those of other parenteral diclofenac products. METHODS: The study comprised three parts: (i) Part 1: an exploratory dose-escalation study to evaluate the tolerability of 25 mg/1 mL, 50 mg/1 mL and 75 mg/1 mL diclofenac sodium formulations administered as a single 5-s i.v. bolus; (ii) Part 2: an exploratory, randomised, crossover study to evaluate the pharmacokinetics of diclofenac following 5-, 15-, and 30-s i.v. bolus injections of diclofenac sodium 75 mg/1 mL; (iii) Part 3: a randomised crossover study to compare the pharmacokinetics of diclofenac following a 5-s i.v. bolus of the 75 mg/1 mL solution to the pharmacokinetics of diclofenac following a 30-min i.v. infusion or intramuscular administration of a 75 mg/3 mL reference formulation. RESULTS: The extent of exposure to diclofenac sodium afforded by the 5-s i.v. bolus of 75 mg/1 mL was equivalent to that provided by the 30-min i.v. infusion of 75 mg/3 mL, since the 90% confidence interval of the geometric mean ratio (GMR) of the area under the curve (AUC) from time 0 to the last plasma concentration time t (AUC0-t) was within the limits 80.00-125.00%, as was the 90% confidence interval of the GMR of the AUC from time 0 extrapolated to infinity (AUC0-∞). The maximum observed plasma concentration (Cmax) was approximately 2.7-fold higher and was achieved earlier (0.05 vs. 0.50 h) with the 1 mL than with the 3 mL formulation, and was similar to data published for a 75 mg/2 mL formulation given as a 15-s i.v. bolus. CONCLUSIONS: Diclofenac sodium 75 mg/1 mL solution administered as a 5-s i.v. bolus was well tolerated. The pharmacokinetic profile, which showed a faster onset and a higher concentration peak than seen for other products and administration routes, suggests a superior analgesic effect.

Pharmacokinetics of a Novel Sildenafil Orodispersible Film Administered by the Supralingual and the Sublingual Route to Healthy Men.

BACKGROUND: Sildenafil was the first selective drug available on the market as oral therapy for erectile dysfunction (ED). A novel sildenafil orodispersible film (ODF) for ED treatment, containing sildenafil citrate, has recently been marketed. OBJECTIVES: Study objective was to investigate sildenafil bioavailability of the novel ODF formulation after sublingual and supralingual administration. METHODS: In this randomised, two-way cross-over study, 12 healthy male volunteers received a single 50 mg sildenafil dose by the sublingual and supralingual administration routes. Plasma sildenafil was determined up to 12 h post-dose. Peak concentration (Cmax) and area under concentration-time curve (AUC0-t) were calculated and compared between the two administration routes by analysis of variance (ANOVA). RESULTS: Sublingual and supralingual administration can be claimed equivalent regarding the extent of sildenafil exposure since AUC0-t 90 % CIs corresponded to 94.90-110.58% and were within the pre-specified acceptance range. Cmax 90% CIs (79.92-125.57%) were only slightly outside the 80.00-125.00% limits, due to the small sample size, while the time to achieve Cmax did not differ between treatments (p = 0.9277). Rate of exposure of the two administration routes was therefore similar. Reported treatment-related adverse events were mild to moderate headache (33.3% of subjects) and vomiting (8.3%). CONCLUSIONS: In healthy men, sublingual and supralingual administration of sildenafil ODF resulted in a remarkably similar pharmacokinetic profile and confirmed the safety of both study treatments. The recently marketed sildenafil ODF, administered by both investigated routes, can provide a valuable alternative to the marketed solid oral forms (tablets) in ED treatment.

Multi-kinetics and site-specific release of gabapentin and flurbiprofen from oral fixed-dose combination: in vitro release and in vivo food effect.

In this work, a fixed-dose combination of gabapentin and flurbiprofen formulated as multilayer tablets has been designed, developed and studied in vitro and in vivo. The aim was to construct a single dosage form of the two drugs, able to perform a therapeutic program involving three release kinetics and two delivery sites, i.e., immediate release of gabapentin, intra-gastric prolonged release of gabapentin and intestinal (delayed) release of flurbiprofen. An oblong three-layer tablet was manufactured having as top layer a floating hydrophilic polymeric matrix for gastric release of gabapentin, as middle layer a disintegrating formulation for immediate release of a gabapentin loading dose and as bottom layer, an uncoated hydrophilic polymeric matrix, swellable but insoluble in gastric fluids, for delayed and prolonged release of flurbiprofen in intestinal environment. The formulations were studied in vitro and in vivo in healthy volunteers. The in vitro release rate assessment confirmed the programmed delivery design. A significant higher bioavailability of gabapentin administered 30min after meal, compared to fasting conditions or to dose administration 10min before meal, argued in favor of the gastro-retention of gabapentin prolonged release layer. The two drugs were delivered at different anatomical sites, since the food presence prolonged the gastric absorption of gabapentin from the floating layer and delayed the flurbiprofen absorption. The attainment of a successful delayed release of flurbiprofen was realized by a matrix based on a polymers' combination. The combined use of three hydrophilic polymers with different pH sensitivity provided the dosage form layer containing flurbiprofen with gastro-resistant characteristics without the use of film coating.

Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease.

Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected-VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one-compartmental model with first-order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73-5.21) L/h, 166 (158-174) L, and 0.582 (0.335-0.829) h-1, respectively. CL/F and Vd/F increased with body weight, while age, gender, renal function, and exposure to levodopa did not influence safinamide PK. The observed ON-time values were adequately described by a linear model, with time in the study period as dependent variable, and rate of ON-time change and baseline plus offset effect as slope and intercept parameters. Safinamide treatment resulted in an increase in ON-time of 0.73 h (week 4), with further ON-time increase with the same slope as placebo. The increase was not influenced by age, levodopa, or safinamide exposure. The population models adequately describe the population PK of safinamide and safinamide effect on ON-time. No dose adjustments in elderly and mild to moderate renally impaired patients are requested.

Pharmacokinetics and Pharmacodynamics of Follicle-Stimulating Hormone in Healthy Women Receiving Single and Multiple Doses of Highly Purified Human Menotrophin and Urofollitrophin.

BACKGROUND AND OBJECTIVE: Highly purified human menotrophin and urofollitrophin preparations obtained from human urine via a novel patented purification method have been tested over a timeframe of 14 years in the studies presented in this article. The objective of the studies was to investigate the pharmacokinetics and the pharmacodynamics of follicle-stimulating hormone (FSH) after single subcutaneous and intramuscular doses and multiple subcutaneous doses of the tested preparations in healthy fertile pituitary-suppressed women. DESIGNS: We performed five open, randomised, crossover, single-dose bioequivalence and/or bioavailability studies and one open, multiple-dose, pharmacokinetics and pharmacodynamics study. STUDY SUBJECTS AND TREATMENTS: The six studies included 121 healthy fertile women taking their usual combined oral contraceptives for 3 months before the study: Study 1: 300 international units (IU) of highly purified menotrophin as single subcutaneous and intramuscular doses. Study 2: 300 IU of highly purified menotrophin (test formulation vs. comparator) as single subcutaneous doses. Study 3: 300 IU of highly purified urofollitrophin (hp-FSH) (test formulation vs. comparator) as single subcutaneous doses. Study 4: 300 IU (2 × 150 IU vs. 4 × 75 IU) of hp-FSH as single subcutaneous doses. Study 5: 225 and 445 IU of hp-FSH as single subcutaneous doses. Study 6: daily 225 IU of hp-FSH as subcutaneous doses for 5 consecutive days. MAIN OUTCOME MEASURES: The main outcome measures were the FSH pharmacokinetic parameters, estradiol concentrations, and the number and size of the follicles. RESULTS: FSH after single subcutaneous and intramuscular injections of menotrophin or urofollitrophin attained a systemic peak (maximum) concentration (C max) that was on average consistent throughout the first four studies and ranged from 4.98 to 7.50 IU/L. The area under the plasma concentration-time curve (AUC) from administration to the last observed concentration time t (AUCt) ranged from 409.71 to 486.16 IU/L·h and the elimination half-life (t ½) ranged from 39.02 to 53.63 h. After multiple doses of urofollitrophin (225 IU) for 5 days, FSH attained a mean C max of 14.93 ± 2.92 IU/L and had an AUC during the time interval τ between two consecutive doses at steady state (AUCτ) of 322.59 ± 57.92 IU/L·h, which was similar to the mean AUCt after a single subcutaneous dose of 225 IU of urofollitrophin in study 5 (306.82 ± 68.37 IU/L·h). CONCLUSIONS: In our studies, the intramuscular and subcutaneous routes of menotrophin were equivalent; both menotrophin and urofollitrophin were bioequivalent to their marketed reference; FSH kinetic parameters following injection of urofollitrophin were dose proportional and independent from the administered concentration; and multiple doses of FSH increased estradiol levels and enhanced growth of follicles with a good dose-response correlation. Local tolerability was excellent throughout the six studies.

Recombinant filgrastim (BK0023) pharmacodynamics and pharmacokinetics after single and multiple escalating doses in an equivalence study in healthy men.

BACKGROUND AND OBJECTIVES: The new filgrastim formulation, BK0023, whose synthesis method is patented, was tested in a phase I clinical study that was aimed at investigating the pharmacodynamic and pharmacokinetic equivalence and the safety of BK0023 in healthy male subjects. METHODS: Single and multiple escalating doses were administered to healthy male volunteers according to a double-blind, randomised, two-way crossover design. Thirty-two subjects received subcutaneous filgrastim 2.5 µg/kg/day for 7 consecutive days in each period, 36 subjects received 5 µg/kg/day for 7 days in each period, and 22 subjects received 10 µg/kg/day for 5 days. Absolute neutrophil count (ANC) and CD34+ cell count were measured in whole blood as primary and secondary pharmacodynamic parameters. Filgrastim concentrations were measured in serum to calculate the primary pharmacokinetic parameters. RESULTS: The maximum ANC and the area under the curve of the ANC after the first dose and to the end of treatment satisfied the equivalence criterion (95 % confidence intervals within 85-115 or 85-117 % in case of log-transformation). At all three dose regimens, BK0023 was also bioequivalent to the reference product in terms of pharmacokinetic profile of serum filgrastim. The frequency of the treatment-emergent adverse events did not differ significantly between treatments, with the most frequent untoward effects being back and bone pain. CONCLUSIONS: Equivalence could be established using both the baseline-adjusted values and the original unadjusted values. The tested formulation at all three dose regimens was also bioequivalent to the reference product in terms of pharmacokinetic profile.

Pharmacodynamics and pharmacokinetics of a novel, low-dose, soft-gel capsule of acetylsalicylic acid in comparison with an oral solution after single-dose administration to healthy volunteers: a phase I, two-way crossover study.

BACKGROUND: Low-dose acetylsalicylic acid (ASA; aspirin) is well-established as a platelet anti-aggregating agent for the secondary prevention of cardiovascular events. OBJECTIVES: The objective of this study was to investigate the non-inferiority of a novel ASA 75 mg soft-gel capsule formulation compared with a marketed powder for oral solution in terms of reduction in serum thromboxane B2 (TXB2), a surrogate for platelet aggregation. Pharmacokinetics and tolerability of the products were also investigated. METHODS: In this randomised, two-way crossover study, 46 male and female healthy subjects received a single dose of the investigational products in two periods separated by a 14-day washout. Serum TXB2 and plasma ASA were determined up to 24 h post-dose. Maximum percentage of TXB2 inhibition (I max) and area under the inhibition-time curve (AUICt) were calculated. Non-inferiority was assumed if the lower limits of the 95 % confidence intervals (CIs) for the two pharmacodynamic parameters were above 85 %. RESULTS: The 95 % CI lower limits were 95.35 % for I max and 86.12 % for AUICt, i.e. within the pre-specified delta. Time to achieve I max did not differ between treatments (p = 0.88). The two formulations were bioequivalent as regards the extent of ASA exposure (area under the plasma concentration-time curve from zero to time t [AUCt] 90 % CIs 96.67-113.37); a delayed ASA absorption (later time to reach maximum plasma concentration [t max], lower maximum plasma concentration [C max]) was observed for the test product. No treatment-related adverse events were reported. CONCLUSIONS: In healthy subjects, the 75 mg soft-gel capsules were not inferior to the oral solution in terms of serum TXB2 inhibition, indicating that the novel formulation could be an effective alternative in the secondary prevention of cardiovascular events.