Pharmacokinetics Analysis Set Research Articles

Relative Bioavailability Study of Midazolam Intramuscularly Administered with the Needle-Free Auto-Injector ZENEO® in Healthy Adults.

Intramuscular (IM) midazolam is indicated for the treatment of status epilepticus. Administration must be efficient to rapidly terminate prolonged seizures and prevent complications. The objective of this study was to compare, in terms of relative bioavailability and bioequivalence, IM midazolam injection by needle-free auto-injector, in different settings, to IM midazolam injection by a conventional syringe and needle. In this open-label, randomized, four-period crossover study, healthy adults received single doses of midazolam (10mg) under fasting conditions. The reference treatment (conventional syringe) was administered once, on bare skin in the thigh. The tested treatment (the needle-free auto-injector ZENEO®) was administered three times: on bare skin in the thigh, on bare skin in the ventrogluteal area, and through clothing in the thigh. Repeated plasma samples were collected to obtain 36-h pharmacokinetic (PK) profiles. Primary PK parameters were area under the plasma concentration-time curve, from time zero to the last measurable time point (AUC0-t) and from time zero to infinity (AUC0-∞), and the maximum observed plasma concentration (Cmax). Forty adults were enrolled and included in the PK analysis set. In all comparisons, the 90% confidence interval (CI) of the least-squares geometric mean ratios for AUC0-t and AUC0-∞ were within the bioequivalence range of 80-125%, with low intra-individual coefficients of variation (< 20.5% for all parameters in all comparisons). Bioequivalence was also met for Cmax in all comparisons except when comparing the tested treatment through clothing versus the reference treatment, where the 90% CI lower limit was slightly outside the bioequivalence range (78.8%). With all tested treatments Cmax was slightly lower, but early mean plasma concentrations (first 10min post-dosing) were higher when compared to the reference treatment. In general, all treatments were well tolerated, with maximum sedation 0.5-1h post-injection. This study establishes that IM midazolam injection on bare skin in the thigh with the ZENEO® is bioequivalent to IM midazolam injection with a syringe and needle. An acceptable relative bioavailability, compatible with emergency practice, was also shown in multiple settings. Higher mean concentrations within the first 10min with the ZENEO® device, and quicker two-step injection suggest a faster onset of action, and thereby an earlier seizure termination, thus preventing the occurrence of prolonged seizure and neurological complications. ClinicalTrials.gov identifier: NCT05026567. Registration first posted August 30, 2021, first patient enrolled May 9, 2022.

Preliminary Analysis Results of a Phase I Study of the FLT3 Inhibitor SKLB1028 in Patients with Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia

Background: Mutations of FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) are associated with poor prognosis. SKLB1028, a novel multikinase inhibitor, has shown exceptional antileukemic activity in mouse xenograft models of FLT3-driven AML. Preclinical data has demonstrated that SKLB1028 has anti-proliferation and pro-apoptosis effects on tumor cells in vitro and in vivo, and prolonged survival in SKLB1028-treated mice has been observed in a dose-dependent manner (Cao et al., Leukemia, 2012). The present study is to assess the safety, tolerability and pharmacokinetics (PK) of SKLB1028 in patients with relapsed/refractory (R/R) FLT3-mutated AML. Here we report the preliminary analysis results of the study. Methods: An open label, 3+3 cohort dose escalation, single arm, phase I study was conducted in adult patients with FLT3-mutated AML who were refractory to or relapsed after ≥ 1 cycle of induction chemotherapy and had an Eastern Cooperative Oncology Group performance status of ≤ 3. Dose cohorts of at least 3 patients received study drug following a sequential dose-escalation design with 20 mg/day as the lowest dose level. For each dose level, patients were firstly given 1 dose of SKLB1028 as an oral capsule followed by 72-hour observation in the single-dose PK period. Then the patients entered the repeated-dose period from day 1, cycle 1, and received oral SKLB1028 once per day in a 28-day cycle. Observations of dose limiting toxicities (DLTs) were recorded through cycle 1. For a specific dose level, if a DLT was observed during the first cycle in 1 patient, 3 additional patients were enrolled at that level. If a second DLT was observed within the same dose cohort, escalation was discontinued, and maximum tolerated dose (MTD) was defined as the immediately lower dose level. Patient who had completed cycle 1 and did not experience a DLT or disease progressionduring cycle 1 could continue receiving SKLB1028, at the discretion of the investigator, until disease progression or intolerable toxicity occurred. The primary endpoints were safety and tolerability. Secondary endpoints included PK and efficacy. Analyses of safety (e.g. DLT and adverse event (AE)) and efficacy parameters (e.g. complete response (CR) and partial response (PR))were performed using descriptive statistics on safety analysis set and full analysis set respectively. PK parameters were estimated using non-compartmental analysis on PK analysis set. Results: Twenty-eight patients with a median age of 50 years (range 19-70 years) were enrolled. The median number of prior regimens was 3.5 (range 1-9). Patients received a median of 2.5 cycles (range 1-15)of therapyin 8 dose cohorts: 20, 40, 80, 120, 160, 200, 250, and 310 mg/day. Three patients discontinued from the study due to AEs. For a subject to be eligible for DLT evaluation, he/she should have received 100% of the planned (28) doses of SKLB1028 in cycle 1, unless the doses were omitted for DLT defining event. Two patients did not complete the first treatment cycle, 1 because of DLT and 1 because of withdrawal of consent. Twenty-seven patients were evaluable for DLT.One patient in the 200 mg cohort experienced DLT (Grade 3 hepatic function abnormal). Among 3 additional patients at this dose level, no DLTs occurred again. The most common treatment-emergent AEs of any grade (regardless of causality) were pyrexia (67.9%), diarrhoea (64.3%), asthenia (53.6%), dizziness (50.0%). There was no death attributed to the use of SKLB1028. The MTD had not been reached. Among the 28 patients treated, only 26 patients were evaluable for efficacy. Two patients were not enlisted due to premature discontinuation of study drug in cycle 1; 1 for DLT and the other for withdrawal of consent. Of 28 patients in the full analysis set, overall response rate (ORR) was 21.4% (6/28) with 1 CR, 5 PR, 20 stable disease and no progressive disease as the best response. One patient achieved CR at the does of 250 mg/day. Of the 5 patients with PR, 1 was in the 160mg cohort, 3 in the 200 mg cohort, and 1 in the 310 mg cohort. The ORR for the 160 mg, 200 mg, 250 mg, and 310 mg cohort of 16 patients was 37.5% (6/16). Conclusions: The results of our preliminary analysis suggested that SKLB1028 is safe, well-tolerated and effective for R/R FLT3-mutated AML patients. Larger studies are needed to more comprehensively assess the safety and efficacy of SKLB1028 in this population. This trial is registered at Clinical Trials.gov, number NCT02859948. Disclosures Yao: CSPC Zhongqi: Employment. Wang:CSPC Zhongqi: Employment. Zhan:CSPC Zhongqi: Employment. Ni:CSPC Zhongqi: Employment. Qiao:CSPC Zhongqi: Employment. Hu:CSPC Zhongqi: Employment.

330P - Pharmacokinetics (PK), safety, and efficacy of [fam-] trastuzumab deruxtecan with OATP1B/CYP3A inhibitors in subjects with HER2-expressing advanced solid tumours

330P - Pharmacokinetics (PK), safety, and efficacy of [fam-] trastuzumab deruxtecan with OATP1B/CYP3A inhibitors in subjects with HER2-expressing advanced solid tumours

A Phase I Comparative Pharmacokinetic and Safety Study of Two Intravenous Formulations of Vinorelbine in Patients With Advanced Non-Small Cell Lung Cancer.

Purpose: The aim of this study was to compare the pharmacokinetics and safety between two vinorelbine formulations [a new oil-in-water emulsion formulation (ANX) versus a previously marketed solution formulation (Navelbine)] in Chinese patients with advanced non-small cell lung cancer (NSCLC). Method: This was a single-center, randomized, open-label study. Eligible patients aged 18–70 years who had histologically or cytologically confirmed NSCLC were enrolled. In cycle 1, the patients alternatively received the two formulations (30 mg/m2, given as a 10-min infusion) with a 7-day interval. Samples for pharmacokinetic analysis were taken during cycle 1. For all subsequent 21-day cycles (maximum four cycles), ANX was administered on days 1 and day 8. Bioequivalence analysis was performed on Cmax, AUClast, and AUCinf. The safety profiles and anti-tumor effects were also determined. Results: From March 2013 to January 2015, 24 patients were enrolled and 20 were eligible for pharmacokinetic evaluation. The 20 subjects in the pharmacokinetic analysis set had a median age of 61 years (range, 37–70 years), and 15 patients were male (75%). Mean vinorelbine Cmax values for ANX and Navelbine were 1,317.40 and 1,446.30 ng/mL, respectively. Corresponding AUClast values were 797.08 and 924.26 ng·h/mL, respectively. AUCinf values were 830.14 and 957.16 ng·h/mL, respectively. Treatment ratios of the geometric means were 90.00% (90% CI, 83.22–99.07%) for Cmax, 86.92% (90% CI, 80.91–93.37%) for AUClast, and 87.44% (90% CI, 82.08–93.16%) for AUCinf. These results met the required 80–125% bioequivalence criteria. The most frequently reported adverse events after vinorelbine administration were neutropenia, leucopenia, neutropenic fever, and constipation. Conclusion: At therapeutic dosage levels, pharmacokinetic behavior and safety profiles were similar for both formulations. Chinese National Registry Code: ChiCTR-IPR-15005856.

A phase I study of TAS-205 in patients with Duchenne muscular dystrophy.

ObjectiveCurrently, the only approved standard Duchenne muscular dystrophy (DMD) treatment in Japan is oral steroids, which have various disadvantages. Previous work has suggested that hematopoietic‐type prostaglandin D synthase (HPGDS), involved in production of the inflammatory mediator prostaglandin D2 (PGD2), might have a role in DMD pathology. We therefore investigated the safety, pharmacokinetics (PK), and pharmacodynamics of a highly selective HPGDS inhibitor (TAS‐205) in Japanese patients with genetically confirmed DMD.MethodsThis was a double‐blind, randomized, placebo‐controlled phase I study to evaluate the use of single or 7‐day repeated doses of TAS‐205 administered orally. The urinary excretion of PGD2 metabolites was also assessed.ResultsThe PK analysis set included 15 and 14 patients in the single‐ and repeated‐dose periods, respectively; the pharmacodynamics set and the safety set included 21 and 19 patients in each period, respectively. The PK of TAS‐205 were linear in the dose range studied (1.67–13.33 mg/kg/dose) and the plasma concentration of TAS‐205 reached steady state by Day 4. TAS‐205 dose‐dependently decreased the urinary excretion of tetranor‐prostaglandin D metabolite at each measurement time point and did not affect the urinary excretion of tetranor‐prostaglandin E metabolite. No clinically significant adverse events were reported after TAS‐205 single or repeated administration.InterpretationWe confirmed the safety and tolerability of TAS‐205 in this study. TAS‐205 decreased the total urinary excretion of PGD2 metabolites in a dose‐dependent manner, suggesting that TAS‐205 might be a therapeutic option to treat DMD patients.

The pharmacokinetics, safety, and tolerability of single, high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma

ABSTRACTObjective: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). Methods: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including Cmax, AUC0–t, AUC0–inf, tmax, and t½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. Results: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (Cmax, AUC0–t, and AUC0–inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t½ values were similar across treatments. Salmeterol Cmax was 20% lower and AUC0–t and AUC0–inf were approximately 50% lower with FS MDPI versus FS DPI. Median tmax and geometric mean t½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. Conclusions: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences.

Population Pharmacokinetic Modeling of Intravenous Asparaginase Erwinia Chrysanthemi: Impact of Varied Infusion Rates on Exposure

Introduction: Asparaginase Erwinia chrysanthemi (Erwinia), an asparagine-specific enzyme indicated as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli-derived asparaginase, is approved in the US for intramuscular and intravenous (IV) administration (Erwinaze USPI 2016). IV administration of proteins, such as asparaginase, may be associated with infusion reactions that may be mitigated by prolongation of the infusion time. Pharmacokinetic (PK) simulations based on a population PK (PPK) model were performed to evaluate PK of IV Erwinia infusions over 2 hours vs 1 hour.Methods: The serum asparaginase activity (SAA) levels from a phase 2, open label, single arm, multicenter, PK study following Erwinia treatment by IV infusion in ALL subjects (1-30 years old) with a previously documented hypersensitivity reaction (≥Grade 2) to pegaspargase were characterized by nonlinear mixed-effects modeling using NONMEM® software. The PPK model included data after 6 doses (1 cycle) of IV Erwinia administered over 1 hour at a 25,000 IU/m2 dose given on a Monday/Wednesday/Friday schedule. The PPK base model for IV Erwinia was identified by comparing different structural and error models. A stepwise approach with forward addition and backward elimination was used to identify important covariates. Visual predictive checks (VPC) were used to demonstrate PPK model predictability. Resampling of the original PK population was used to create a virtual patient population (n = 9999) to simulate average SAA levels and corresponding variability for both 1- and 2-hour IV infusion regimens, summarized by 95% prediction intervals.Results: The PK analysis set contained 24 subjects with 331 evaluable PK samples collected over 6 cycles of therapy. The majority of PK samples were collected during Cycle 1 (55%) with the majority of subjects being male (62.5%) and Caucasian (79%). The median (range) for age was 6.5 years (1-17) and for weight 21.4 kg (10.9 to 118.3). Trough SAA levels ≥0.1 IU/mL at 48 hours post dose 5 (primary endpoint) were achieved by 83% of the evaluable subjects in Cycle 1 (95% CI: 63%-95%). A 2-compartment model with inter-individual variability on clearance (CL) was found to best describe the PK of Erwinia. The final model for CL was:CL [mL/hr] = 123[mL/hr] + 17[mL/hr] * (weight [kg] / 21.4 kg)The central and peripheral volumes of distribution were 1.59 L and 0.154 L, respectively. As more PK samples were available for Cycle 1, separate proportional error models partitioned residual variability for Cycle 1 (36.6%) vs Cycles 2-6 (48.6%). The derived mean half-life estimate (CV%) was 7.51 hours (23.9%). The VPC demonstrated the bulk (>90%) of the observed SAA falling within the 95% PPK model-based simulation prediction intervals. The PPK model-based SAA simulation results after 1- and 2-hour IV infusions are displayed in Table 1 and Figure 1. Despite different initial rates of rise, similar SAA vs time profiles were observed when comparing 1- vs 2-hour infusion durations (Figure 1), with a similar number of subjects achieving therapeutic trough levels ≥ 0.1 IU/mL (Table 1).Conclusions: The final PPK model demonstrated a good ability to predict SAA allowing estimation of elimination characteristics and the application of subsequent model-based simulations.The PK simulations for 1- vs 2-hour IV Erwinia showed similar mean 48-hour trough SAA levels, as well as similar proportions of subjects having therapeutic 48-hour trough SAA ≥ 0.1 IU/mL. Based on these PK results, duration of IV Erwinia could be increased from 1 to 2 hours, which may reduce symptoms of infusion reactions. Reducing infusion reactions may potentially enablemore patients to complete Erwinia treatment. Upon approval from FDA in 2016, IV infusion duration in the Erwinaze USPI was revised from 1 hour to 1-2 hours; this is also consistent with the updated Children’s Oncology Group protocols.Support: Jazz Pharmaceuticals. [Display omitted] [Display omitted] DisclosuresZomorodi:Jazz Pharmaceuticals: Employment, Equity Ownership. Dumas:Quintiles: Employment; Jazz Pharmaceuticals: Consultancy. Berry:Quintiles: Employment; Jazz Pharmaceuticals: Consultancy. Johnston:Jazz Pharmaceuticals: Consultancy; Quintiles: Employment. Eller:Jazz Pharmaceuticals: Employment, Equity Ownership.

A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study.

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax) to peak concentration (Cmax) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, Cmax, Tmax or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, −30%; ER‐Tac:LCPT, −36%. After exposure normalization, Cmax was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; Cmin was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac.

Abstract 4640: Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258)

Abstract Background Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. A phase 3 study in renal cell carcinoma used a capsule (cap) formulation of dovitinib. However, the planned commercial formulation is a tablet (tab). Therefore, this study evaluated the bioequivalence of the tab and cap formulations using a crossover design. Methods Patients (pts) ≥ 18 years of age with advanced solid tumors (excluding breast cancer) were randomized to receive caps or tabs (500 mg po once daily, 5 days on/2 days off) for 3 weeks, followed by the same dose and schedule of the other formulation for 1 week. Following the bioequivalence phase, pts could continue to receive dovitinib caps (500 mg once a day, 5 days on/2 days off). Blood samples for dovitinib plasma concentrations were collected before and after the fifth dose in weeks 3 and 4. The pharmacokinetic (PK) analysis set (PAS) comprised pts with ≥ 2 evaluable PK profiles following cap and tab administration, who did not vomit ≤ 4 hours after dosing on blood collection days and received ≥ 7 of the first 10 doses and 4 consecutive days of dosing prior to blood collection. A linear mixed-effects model was fitted to log-transformed parameters (area under the curve [AUClast] and maximal concentration [Cmax]). Results A total of 173 pts were randomized to receive the cap/tab sequence (n = 88) or the tab/cap sequence (n = 85). The median age was 60 years, and the most common primary sites of cancer were colon (n = 48), lung (n = 18), and rectum (n = 14). Sixty-nine pts were in the PAS (32 in the cap/tab sequence and 37 in the tab/cap sequence). The most common reason for PAS exclusion was dose interruption due to disease progression or adverse events (AEs). Geometric means of PK parameters were similar for the tab vs cap formulations: AUClast (5379 vs 5705 h·ng/mL), Cmax (247 vs 252 ng/mL), half-life (14.5 vs 15.3 h), oral clearance (89.5 vs 82.5 L/h), and apparent volume of distribution (1876 vs 1823 L). The geometric mean ratios (90% CI) for AUClast and Cmax comparing tab vs cap were 0.95 (0.88-1.01) and 0.98 (0.91-1.05), respectively. In pts who received at least 1 dose of dovitinib throughout the entire study (including the postbioequivalence phase; n = 168), the most common AEs suspected to be related to study drug (any grade) were diarrhea (58.9%), nausea (50.0%), fatigue (42.3%), vomiting (41.7%), and decreased appetite (20.8%). Grade 3/4 AEs were &amp;lt; 5% except for fatigue (11.9%), diarrhea (5.4%), and hypertension (5.4%). Conclusions The tab and cap formulations were bioequivalent. The safety profile was similar to that observed in other dovitinib studies in pts with advanced solid tumors. The tab formulation is used in selected current studies and will be used in future clinical dovitinib studies. Citation Format: John Sarantopoulos, Sanjay Goel, Vincent Chung, Pamela Munster, Shubham Pant, Manish Patel, Jeffrey Infante, Hussein Tawbi, Carlos Becerra, Justine Bruce, Fairooz Kabbinavar, Howard Kaufman, A. Craig Lockhart, Eugene Tan, Shu Yang, Mariama Diallo, Jeffrey Scott, Sunil Sharma. Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4640. doi:10.1158/1538-7445.AM2014-4640

Comparative Pharmacokinetics and Bioavailability of Gemifloxacin Administered as an Intravenous 200 mg Formulation or an Oral 320 mg Tablet

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent, which has potent activity against most Gram-negative and Gram-positive organisms. It is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The aim of this study was to assess the clinical potential of a new gemifloxacin 200 mg intravenous formulation by comparing its pharmacokinetic characteristics with those of the branded Factive(®) gemifloxacin tablet. A single-dose, open-label, randomized-sequence, two-period crossover study was performed with 17 healthy male volunteers. The two treatment periods were separated by a 1-week washout period. Blood samples were taken for up to 48 h post-dose. Plasma gemifloxacin concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. To calculate the pharmacokinetic parameters, noncompartmental analysis was performed. The two formulations were considered to be pharmacokinetically equivalent if the 90 % confidence intervals (CIs) of the log-transformed ratios (intravenous/oral formulations) of the area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and the AUC from time zero to infinity (AUC∞) were within the standard bioequivalence range (0.8-1.25). Safety and tolerability were evaluated on the basis of physical examinations, vital signs, electrocardiograms, clinical laboratory tests and adverse event monitoring. Seventeen subjects were enrolled, and 15 subjects completed the study. Sixteen subjects received intravenous 200 mg gemifloxacin and 15 received oral 320 mg gemifloxacin. The 15 subjects in the pharmacokinetic analysis set had a mean (standard deviation [SD]) age, height and weight of 27.2 (5.3) years, 173.5 (4.4) cm and 67.3 (7.4) kg, respectively. Both formulations had similar pharmacokinetic profiles. For the intravenous formulation, the mean (SD) AUClast, AUC∞ and maximum plasma concentration (C max) values were 9.12 (4.03) μg·h/mL, 9.26 (4.07) μg·h/mL and 2.90 (1.65) μg/mL, respectively, while these values for the oral formulation were 9.44 (3.34) μg·h/mL, 9.60 (3.49) μg·h/mL and 2.03 (0.95) μg/mL, respectively. For the intravenous and oral formulations, the median (range) time to reach C max (t max) values were 0.9 (0.7-1.0) and 1.0 (0.5-2.0) h, respectively. The mean relative bioavailability was 68.99 %. The 90 % CI of the ratios of the log-transformed values of AUClast and AUC∞ was 0.82-1.07. There were no serious adverse events. The intravenous and oral formulations were associated with treatment-emergent adverse event incidences of 63 % (10/16) and 13 % (2/15), respectively. After the intravenous formulation was administered, application site pain and paraesthesia were the most frequently reported adverse events (31 and 25 %, respectively). All adverse events resolved spontaneously without treatment. Intravenous 200 mg and oral 320 mg formulations of gemifloxacin are equivalent in terms of AUC following a single dose in healthy male subjects.

Pharmacokinetics, Safety, and Efficacy Of Long-Lasting Recombinant Factor IX Fc Fusion Protein (rFIXFc) In Adolescent Subjects With Hemophilia B: A Subgroup Analysis Of The B-LONG Study

Pharmacokinetics, Safety, and Efficacy Of Long-Lasting Recombinant Factor IX Fc Fusion Protein (rFIXFc) In Adolescent Subjects With Hemophilia B: A Subgroup Analysis Of The B-LONG Study

Tacrolimus Pharmacokinetics of Once- Versus Twice-Daily Formulations in De Novo Kidney Transplantation

Tacrolimus is a well-established immunosuppressive agent for the treatment and prevention of solid organ graft rejection. It is available as an immediate-release, twice-daily formulation (Tacrolimus BID) and a prolonged-release, once-daily formulation (Tacrolimus QD). In a previous study of the pharmacokinetics (PK) of these formulations, mean systemic exposure [area under the curve from 0 to 24 hours (AUC0-24)] of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than for Tacrolimus BID; by day 14, systemic exposure was similar; however, the mean dose of Tacrolimus QD was higher to achieve similar systemic exposure as Tacrolimus BID. To further compare the PK of the tacrolimus formulations during the first 2 weeks posttransplant, a substudy was performed in a subset of patients enrolled into a phase III trial in de novo kidney transplant recipients comparing Tacrolimus QD and Tacrolimus BID. To minimize the difference in exposure observed in the earlier study, tacrolimus therapy was initiated before transplant. The PK analysis set comprised 34 patients (17 patients per treatment group) who had 4 complete PK profiles and no major PK-related protocol violations. Mean AUC0-24 of tacrolimus on day 1 was approximately 16% lower for Tacrolimus QD than for Tacrolimus BID, although by day 3 onward, the exposure was similar between treatment groups. Analysis of dose-normalized AUC0-24 (dose normalized to 0.1 mg/kg) showed a similar pattern. There was a good correlation between AUC0-24 and concentration of tacrolimus at 24 hours postdose for both formulations (Tacrolimus QD, r = 0.87; Tacrolimus BID, r = 0.92), and the slope of the line of best fit was similar. These results suggest that initiating tacrolimus therapy before transplant reduces the difference in exposure between Tacrolimus QD and Tacrolimus BID.

Latanoprost Systemic Exposure in Pediatric and Adult Patients with Glaucoma: A Phase 1, Open-Label Study

To evaluate short-term safety and steady-state systemic pharmacokinetics (PK) of latanoprost acid in pediatric subjects with glaucoma or ocular hypertension who received the adult latanoprost dose. Phase 1, open-label, multicenter study. Pediatric patients of 3 age groups (<3, 3-<12, and 12-<18 years) and adults (≥18 years) receiving latanoprost ophthalmic solution 0.005% once daily in 1 or both eyes for ≥2 weeks. Latanoprost was administered in both eyes each morning post-screening. Subjects returned 3 to 28 days later for evaluation of plasma concentrations, withholding morning latanoprost. At the clinic, a single drop of latanoprost ophthalmic solution was instilled into both eyes. Plasma latanoprost acid concentrations were collected predose and 5, 15, 30, and 60 minutes after administration. Latanoprost acid plasma exposure. The evaluable PK analysis set included data from 39 of 47 enrolled subjects. The median peak plasma concentration value was higher in the <3-year age group (166 pg/ml) versus other groups (49, 16, and 26 pg/ml for the 3-<12-year, 12-<18-year, and ≥18-year age groups, respectively). The median area under the concentration-time curve from zero to last measurable concentration value was also higher in the <3-year age group (2716 pg/min/ml) versus other groups (588, 106, and 380 pg/min/ml for the 3-<12-year, 12-<18-year, and ≥18-year age groups, respectively). Latanoprost acid was rapidly eliminated from the blood, with plasma concentrations undetectable within 10 to 30 minutes postdose in all but the <3-year age group. There were no discontinuations or dose reductions due to adverse events or treatment-emergent adverse events. Latanoprost acid systemic exposure was higher in younger children versus adolescents and adults, attributed primarily to lower body weight and smaller blood volume. Latanoprost acid was eliminated rapidly in all age groups and resulted in only a brief period of systemic exposure after once-daily dosing. Higher systemic exposure was not accompanied by adverse events, and on the basis of extrapolation of safety data from adults, this pilot study suggests an adequate safety margin for systemic adverse effects with use of the adult topical dose of latanoprost in pediatric patients. Proprietary or commercial disclosures may be found after the references.