Single-dose Clinical Trial Research Articles

Pharmacokinetic Profile and Comparative Bioavailability of an Oral Fixed-Dose Combination of Metformin and Acetylsalicylic Acid (Aspirin).

Patients with diabetes face a 2-4-fold greater cardiovascular risk compared to those without diabetes. Both metformin and acetylsalicylic acid (aspirin) treatment have demonstrated a significant reduction in this risk. This single-center, open-label, sequence randomized, 2×2 crossover, single-dose clinical trial evaluated the pharmacokinetics profile and comparative bioavailability of a novel oral fixed-dose combination (FDC) of metformin/acetylsalicylic acid (500/100mg tablet) versus the reference mono-drugs administered concomitantly, metformin 500mg tablet and acetylsalicylic acid 100mg tablet, in 22 healthy Mexican adult volunteers under fasting conditions. Blood samples were collected predose and at specified intervals across a 24-hour period following administration and were analyzed for metformin and salicylic acid using high-performance liquid chromatography coupled with tandem mass spectrometry. Test products were considered to have comparative bioavailability if confidence intervals of natural log-transformed (maximum plasma drug concentration (Cmax), (area under the plasma drug concentration-time curve form 0 up to last sampling time (AUC0 -t), and (area under the plasma drug concentration-time cruve from 0 up to infinity (AUC0 ∞) data were within the range of 80%-125%. The results obtained from the present clinical study demonstrate the comparative bioavailability of the FDC when compared with the coadministration of reference mono-drugs. There were no adverse events or adverse reactions reported throughout the study.

Use of Exposure Data to Establish Causality in Drug-Adverse Event Relationships: An Example with Desvenlafaxine.

Causality algorithms help establish relationships between drug use and adverse event (AE) occurrence. High drug exposure leads to a higher likelihood of an AE being classified as an adverse drug reaction (ADR). However, there is a knowledge gap regarding what concentrations are predictive of ADRs, as this has not been systematically studied. In this work, the Spanish Pharmacovigilance System (SEFV) algorithm was used to define the relationship between the AE occurrence and drug administration in 178 healthy volunteers participating in five desvenlafaxine single-dose clinical trials, a selective serotonin and norepinephrine reuptake inhibitor that may cause dizziness, headache, nausea, dry mouth, constipation and hyperhidrosis. Eighty-three subjects presented 172 AEs that were classified as possible (101), conditional (31), unrelated (24) and probable (16). AUC∞ and Cmax were significantly higher in volunteers with vs. without ADRs (5981.24 ng·h/mL and 239.06 ng/mL and 4770.84 ng·h/mL and 200.69 ng/mL, respectively). Six of 19 subjects with conditional AEs with an SEFV score of 3 points presented an AUC∞ ≥ 6500 ng·h/mL or a Cmax ≥ 300 ng/mL (i.e., above percentile 75) and were summed one point on their SEFV score and classified as "possible" (4 points), improving the capacity of ADR detection.

Development and Bioequivalence of 3D-Printed Medication at the Point-of-Care: Bridging the Gap Toward Personalized Medicine.

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. Three-Dimensional (3D) printing of medicines, which enables small-scale manufacturing at the point-of-care, can fulfill this unmet clinical need. This study investigates the feasibility of developing a 3D-printed tablet formulation at the point-of-care which complies to quality requirements for clinical practice, including bioequivalence. Development, manufacturing, and quality control of the 3D-printed tablets was performed at the manufacturing facility and laboratory of the department of Clinical Pharmacy and Toxicology at Leiden University Medical Center. Sildenafil was used as a model drug for the tablet formulation. Along with the 3D-printed tablets a randomized, an open-label, 2-period, crossover, single-dose clinical trial to assess bioequivalence was performed in healthy adults. Bioequivalence was established if areas under the plasma concentration curve from administration to the time of the last quantifiable concentration (AUC0-t ) and maximum plasma concentration (Cmax ) ratios were within the limits of 80.00-125.00%. The manufacturing process provided reproducible 3D-printed tablets that adhered to quality control requirements and were consequently used in the clinical trial. The clinical trial was conducted in 12 healthy volunteers. The 90% confidence intervals (CIs) of both AUC0-t and Cmax ratios were within bioequivalence limits (AUC0-t 90% CI: 87.28-104.14; Cmax 90% CI: 80.23-109.58). For the first time, we demonstrate the development of a 3D-printed tablet formulation at the point-of-care that is bioequivalent to its marketed originator. The 3D printing of personalized formulations is a disruptive technology for compounding, bridging the gap toward personalized medicine.

Interim results of Transpher A, a multicenter, single-dose clinical trial of UX111 gene therapy for Sanfilippo syndrome type A (mucopolysaccharidosis IIIA)

Interim results of Transpher A, a multicenter, single-dose clinical trial of UX111 gene therapy for Sanfilippo syndrome type A (mucopolysaccharidosis IIIA)

1159. Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Pediatric Participants With Confirmed or Suspected Gram-negative Bacterial Infections: A Phase 1b, Open-label, Single-Dose Clinical Trial

BackgroundImipenem/cilastatin/relebactam (IMI/REL) is approved for treating hospital-acquired/ventilator-associated bacterial pneumonia, complicated urinary tract infection, and complicated intra-abdominal infection in adults. This study assessed single-dose pharmacokinetics (PK), safety, and tolerability of IMI/REL in neonatal and pediatric participants with confirmed or suspected gram-negative bacterial infections.MethodsThis was a phase 1, open-label, non-comparative study (NCT03230916). Age- and weight-adjusted dosing is summarized in Table 1. The primary objective was to characterize the PK profiles for imipenem and relebactam after a single intravenous dose of IMI/REL. PK parameters were analyzed using population modeling. The PK target for imipenem was the percent time of the dosing interval that the unbound plasma concentration exceeded the minimum inhibitory concentration (%fT >MIC) of ≥30% (MIC used, 2 µg/mL). The PK target for relebactam was an area under the curve (AUC)/MIC ratio >8 (MIC used, 2 µg/mL), corresponding to AUC0-24h >58.88 μM∙h. Safety and tolerability were assessed for up to 14 days after drug infusion. ResultsOf the 46 participants who received IMI/REL, 42 were included in the PK analysis. The mean plasma concentration-time profiles for imipenem and relebactam were generally comparable across age cohorts (Figure). For imipenem, the geometric mean %ƒT >MIC ranged from 50% to 94% and the mean maximum concentration (Cmax) ranged from 65 μM to 126 μM (Table 2). For relebactam, the geometric Cmax ranged from 33 μM to 87 μM and mean AUC0-6h ranged from 51 μM·h to 159 μM·h across the age cohorts (Table 2). IMI/REL was well tolerated with 8 (17.4%) participants experiencing ≥1 adverse events (AE) and 2 (4.3%) participants experiencing AE that were deemed drug related by the investigator. Drug-related AE were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, and diarrhea, which were non-serious, mild in severity, and resolved within the follow-up period of 14 days.Figure 1 ConclusionImipenem and relebactam exceeded the pediatric plasma PK targets across pediatric age cohorts in the study; the single doses of IMI/REL were well tolerated. These results will inform IMI/REL dose selection for further pediatric clinical evaluation.Disclosures Camilla Tøndel, MD, PhD, Merck & Co., Inc., (Grant/Research Support) Emmanuel Roilides, MD, PhD, FIDSA, FAAM, FESCMID, FECMM, FISAC, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Matthew S. Kelly, MD, MPH, Merck Sharp & Dohme Corp. (Consultant, Grant/Research Support) Munjal Patel, PhD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Pavan Vaddady, PhD, Merck Sharp & Dohme Corp. (Employee) Alok Maniar, MD, MPH, Merck Sharp & Dohme Corp. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck Sharp & Dohme Corp. (Employee, Shareholder) Joan R. Butterton, MD, Merck Sharp & Dohme Corp. (Employee, Shareholder) Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck (Employee)

Acute toxicity is a dose-limiting factor for intravenous polymyxin B: A safety and pharmacokinetic study in healthy Chinese subjects

ObjectivesPolymyxin B is a last-line antibiotic for multidrug-resistant gram-negative bacterial infections. However, limited safety and pharmacokinetic information is available. We investigated the safety and pharmacokinetics of intravenous polymyxin B in healthy subjects. MethodsAn open-label, single-dose clinical trial was conducted in healthy Chinese subjects. Polymyxin B (sulphate) was administered intravenously at 0.75 or 1.5 mg/kg (n = 10 per dose, 5 males and 5 females) to examine the safety and pharmacokinetics. ResultsOne female subject in the 1.5-mg/kg group discontinued due to abdominal pain during administration. The most frequently reported adverse events were perioral paraesthesia, dizziness, and numbness of extremities (7/10 subjects in the 0.75-mg/kg group, all subjects in the 1.5-mg/kg group). All neurotoxicity-related events dissipated without treatment within a maximum of 23 h. Notably, abdominal pain (3/5) and vulvar pruritus (2/5), colpitis (2/5) or abnormal uterine bleeding (1/5) were reported in female subjects receiving the 1.5-mg/kg dose. In the 0.75-mg/kg group, the total clearance, volume of distribution and half-life of polymyxin B were 0.028±0.002 L/h/kg, 0.219±0.023 L/kg and 5.44±0.741 h, respectively; similar values were observed in the 1.5-mg/kg group. Urinary recovery was 3.7 ± 1.1% and 8.1 ± 1.3% in the 0.75- and 1.5-mg/kg groups, respectively. Population pharmacokinetics of polymyxin B was consistent with a three-compartment model. The clearance and distribution of the central compartment were 0.027 L/h/kg and 0.071 L/kg, respectively. ConclusionsThis study is the first to examine the safety and pharmacokinetics of polymyxin B in healthy subjects. Our results highlight that acute toxicity is a dose-limiting factor for intravenous polymyxin B.

Impact of Bariatric Surgery on the Pharmacokinetics Parameters of Amoxicillin.

Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs, such as antibiotics. The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass (RYGB) surgery is unknown. The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of amoxicillin. This study was performed as a randomized, open-label, single-dose clinical trial, with two periods of treatment, in which obese subjects (n = 8) received an amoxicillin 500mg capsule orally before and 2months after the RYGB surgery. The amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry (LC-MS/MS). After the surgery, the mean weight loss was 17.03 ± 5.51kg, and mean body mass index (BMI) decreased from 46.21 ± 2.82 to 38.82 ± 3.32kg/m2. The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration (AUC0-tlast) increased significantly (3.5-fold); the maximum plasma concentration (Cmax) increased 2.8-fold after the bariatric surgery. No correlation was found between amoxicillin absorption, BMI, and weight loss percentage. The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery. However, despite this increase, its exposure was lower than the values reported for non-obese volunteers. Identifiers: NCT03588273.

Clinical Pharmacology of Fast-Acting Insulin Aspart Versus Insulin Aspart Measured as Free or Total Insulin Aspart and the Relation to Anti-Insulin Aspart Antibody Levels in Subjects with Type 1 Diabetes Mellitus

BackgroundFast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp.MethodsFree and total IAsp concentrations and anti-IAsp antibodies were determined in adults with type 1 diabetes mellitus receiving subcutaneous faster aspart and/or IAsp in four single-dose clinical pharmacology trials (n = 175) and a 26-week phase IIIa trial (n = 1040). Pharmacodynamics were assessed by euglycaemic clamp or meal test, respectively.ResultsThe pharmacokinetic profile was left-shifted and early exposure was greater with faster aspart versus IAsp independent of free or total IAsp assay. The faster aspart-IAsp difference in the time to 50% of maximum IAsp concentration in the early part of the pharmacokinetic profile (tEarly 50 % Cmax) [95% confidence interval (CI)] was − 8.8 [− 10.0 to − 7.5] and − 7.6 [− 8.8 to − 6.4] min for free and total IAsp, respectively. The faster aspart/IAsp ratio for the area under the concentration–time curve (AUC) for IAsp from time zero to 30 min (AUCIAsp,0–30 min) [95% CI] was 1.88 [1.74–2.04] and 1.77 [1.64–1.90] for free and total IAsp. Higher anti-IAsp antibody levels were associated with a lower ratio of free/total IAsp for the total AUC for IAsp (AUCIAsp,0–t). Early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 60 min [AUCGIR,0–60 min]) was greater by 25–44% for faster aspart versus IAsp independent of anti-IAsp antibody levels. Total glucose-lowering effect (total AUC for GIR [AUCGIR,0–t]) in a clamp and 1-h postprandial glucose increment in a meal test appeared essentially unaffected by anti-IAsp antibodies.ConclusionsFaster aspart provides accelerated pharmacokinetics versus IAsp regardless if based on free or total IAsp assay. Higher anti-IAsp antibodies increase total IAsp concentrations but do not influence faster aspart nor IAsp pharmacodynamics.ClinicalTrials.gov identifiersNCT01618188, NCT02003677, NCT01934712, NCT02568280, NCT01831765.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0718-6) contains supplementary material, which is available to authorized users.

A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma

BackgroundThis study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model.MethodsThis was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge.ResultsNo significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo.ConclusionsS1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated.Trial registrationClinicalTrials.gov, NCT02334553. Registered on 12 November 2014.

Propranolol for treating emotional, behavioural, autonomic dysregulation in children and adolescents with autism spectrum disorders.

To date, there is no single medication prescribed to alleviate all the core symptoms of Autism Spectrum Disorder (ASD; National Institute of Health and Care Excellence, 2016). Both serotonin reuptake inhibitors and drugs for psychosis possess therapeutic drawbacks when managing anxiety and aggression in ASD. This review sought to appraise the use of propranolol as a pharmacological alternative when managing emotional, behavioural and autonomic dysregulation (EBAD) and other symptoms. Sixteen reports examined the administration of propranolol in the context of ASD. Sixteen reports broadly covered cognitive domains, neural correlates, and behavioural domains. From the eight single-dose clinical trials, propranolol led to significant improvements in cognitive performance - verbal problem solving, social skills, mouth fixation, and conversation reciprocity; and changes in neural correlates - improvement in semantic networks and functional connectivity. The remaining eight case series and single case reports showed improvements in EBAD, anxiety, aggressive, self-injurious and hypersexual behaviours. Additionally, propranolol significantly improved similar behavioural domains (aggression and self-injury) for those with acquired brain injury. This review indicates that propranolol holds promise for EBAD and cognitive performance in ASD. Given the lack of good quality clinical trials, randomised controlled trials are warranted to explore the efficacy of propranolol in managing EBAD in ASD.

Abstract P2-01-05: A phase II clinical trial of VST-1001 (dilute fluorescein) in lymphatic mapping and sentinel lymph node localization in clinically node negative breast cancer

Abstract Background: Combined use of a radiocolloid and a vital blue dye is recommended for accurate lymphatic mapping and sentinel lymph node (SLN) identification in breast cancer. However, vital blue dyes can cause tattooing, skin necrosis and severe allergic reactions. Moreover, the vital blue dyes are only able to detect 70% or less of SLNs in large multi-center trials. Hence, there is an unmet need to develop new lymphatic mapping agents that could potentially replace vital blue dyes. We have previously, in a Phase I trial, reported on the safety of VST-1001 (dilute fluorescein) in SLN identification. Here we report the Phase II data of VST-1001 and direct visualization devices in lymphatic mapping, SLN identification, and safety in clinically node negative breast cancer. Methods: This prospective Phase II, multi-center, non-randomized, single-arm, open-label, single-dose clinical trial enrolled patients (pts) with DCIS and clinical stage I/II breast cancer eligible for SLN biopsy. All pts had SLN localization with technetium-99m-sulfur colloid (Tc99mSC) and intraoperative lymphatic mapping with 0.1% VST-1001 injected peritumorally, periareolarly, and/or intradermally. SLN radioactivity was identified with a gamma probe, and VST-1001 fluorescence was induced by light emitting diodes and detected as yellowish-green fluorescence in the visible light range with notch filter spectacles. The primary endpoint was the ability of VST-1001 to localize lymph nodes. SLN concordance of Tc99mSC radioactivity and VST-1001 fluorescence, and safety were also assessed. Results: Eighty-seven women and 2 men with a median age of 60 yrs (range, 37-77) were enrolled. Primary tumor T-stage was: 12.4% T0, 62.9% T1, 23.6% T2, and 1.1% T3. Of the 89 pts, 87 (97.8%) had at least 1 radioactive SLN, and 86 (96.6%) at least 1 fluorescent SLN. Of a total of 198 SLN identified (mean 2.2 SLN/pt), 74.2% were fluorescent and radioactive, 11.6% were radioactive only, 8.6% were fluorescent only, and 5.1% were not radioactive or fluorescent. 82.8% of all SLNs were fluorescent. Twelve (13.5%) pts had microscopic metastatic breast cancer in 14 (7.1%) SLNs. Of the 14 SLNs with metastasis, 12 (85.7%) were both radioactive and fluorescent, 1 (7.1%) fluorescent only and 1 (7.1%) not radioactive or fluorescent and only suspicious on palpation. The fluorescent only SLN was identified in a patient with only 1 SLN and without VST-1001 the metastasis would have been missed. The only adverse event related to VST-1001 was intraoperative grade 2 allergic reaction of the ipsilateral breast in one pt. Intravenous anti-histamines were administered and the erythema resolved. Conclusions: VST-1001 safely localized lymph nodes in breast cancer. VST-1001 was able to localize lymph nodes that were not radioactive and had a high co-localization concordance with Tc99mSC. VST-1001 also appears to have a higher rate of SLN localization compared to that historically reported for vital blue dyes. In light of these data, VST-1001 may be an alternative SLN localizing agent to be used in conjunction with Tc99mSC in breast cancer pts, eliminating many of adverse events observed when using vital blue dyes without compromising SLN identification. Citation Format: Ross MI, Black DM, Mittendorf EA, Porretta JM, Bedrosian I, Caudle AS, Hwang RF, Meric-Bernstam F, Babiera GV, Brulotte M, Andtbacka RHI, Matsen CB. A phase II clinical trial of VST-1001 (dilute fluorescein) in lymphatic mapping and sentinel lymph node localization in clinically node negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-05.

Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial.

In this clinical trial, we investigated the blood glucose (BG)‐lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline‐adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long‐term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase‐4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the β‐cell protective properties of DXM.

Simulation studies on the estimation of total area under the curve in the presence of right-tailed censoring

The effect of extrapolated area (%AUCextrap) on estimating mean AUCinf in a simulated single-dose clinical trial was examined. Concentration-time (C-t) profiles from 12 to 36 subjects for 1- and 2-compartment models after single dose administration were simulated with increasing right-tailed censoring. Each subject's %AUCextrap and AUCinf was calculated using eight different methods, including noncompartmental analysis (NCA), population-based methods, and maximum likelihood (ML) accounting for censoring. Each method's geometric mean AUCinf and percent relative error (PRE) from the true AUCinf was calculated. This was repeated 100 times and the mean PRE (MPRE) was calculated. Mean %AUCextrap ranged from 1 to ~30 % for the 1-compartment and 2 to 32 % for the 2-compartment model at the lowest and highest degree of censoring, respectively. NCA methods using all subjects to estimate the population mean AUCinf had similar or less bias (within ± 20 %) than when those subjects with >20 % %AUCextrap were removed. Using Cpred compared to Clast in the calculation of individual AUCinf resulted in no performance improvement. Linear mixed effects models to estimate λz and ML methods accounting for censoring resulted in either no improvement or increased bias when censoring was high. Population pharmacokinetic method bias was dependent on the nature of the C-t profile. When the C-t profile declined biphasically, population models had higher bias than NCA methods but were superior when the C-t profile decline in a log-linear manner. It is recommended that subjects with high %AUCextrap should not be removed from the estimation of mean AUCinf in NCA analyses.

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C(max) than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China

To describe the population pharmacokinetic profile of modafinil acid and to compare the extent of metabolism of modafinil into modafinil acid in 5 major ethnic groups (Han, Mongolian, Korean, Uygur, and Hui) of China. In a multi-center, open-label, single dose clinical trial, 49 healthy volunteers from the 5 ethnic groups received 200 mg of modafinil orally. Blood samples for pharmacokinetic evaluation of modafinil and modafinil acid were drawn before and at different time after the administration. Systematic population pharmacokinetic (PopPK) modeling for modafinil acid was conducted, integrating with our previous PopPK model for modafinil. The influence of ethnicity, gender, height, body weight and body mass index (BMI) was estimated. The extent of metabolism of modafinil into modafinil acid, expressed as the relative conversion fraction, was estimated and compared among the 5 ethnic groups. When combined with the PopPK model of modafinil, the concentration of modafinil acid versus time profile was best described with a one-compartment model. The typical clearance and volume of distribution for modafinil acid were 4.94 (l/h) and 2.73 (l), respectively. The Korean group had 25% higher clearance, and the Uygur and Hui groups had 12% higher clearance than the Han group. The median for the relative conversion fraction was 0.53 for Koreans, and 0.24 for the other 4 ethnicities. Ethnicity has significant influence on the clearance of modafinil acid. When patients in the 5 ethnic groups are administered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered.

Assessment of the Efficacy and Safety Profiles of Aspirin and Acetaminophen With Codeine: Results From 2 Randomized, Controlled Trials in Individuals With Tension-Type Headache and Postoperative Dental Pain

BackgroundAspirin is a widely used NSAID that has been extensively studied in numerous conditions. Nonprescription analgesics, such as aspirin, are frequently used for a wide variety of common ailments, including conditions such as dental pain and tension-type headache. ObjectiveWe sought to compare the efficacy and safety profiles of aspirin, acetaminophen with codeine, and placebo in the treatment of post-operative dental pain and tension-type headache. MethodsThese were 2 randomized, double-blind, placebo-controlled, single-dose clinical trials that assigned participants (2:2:1) to receive either aspirin (1000 mg), acetaminophen (300 mg) with codeine (30 mg), or placebo. The primary efficacy end point was the sum of pain intensity differences from baseline (SPID) over 6 hours for the dental pain study and over 4 hours for the tension-type headache study. Other common analgesic measures, in addition to safety, were also evaluated. ResultsThe results of the dental pain study for aspirin and acetaminophen with codeine suggest statistically significant efficacy for all measures compared with placebo at all time points. Aspirin provided statistically significant efficacy compared with acetaminophen with codeine for SPID0–4 (P = 0.028). In the tension-type headache study, aspirin and acetaminophen with codeine provided statistically significant efficacy compared with placebo for SPID0–4 and SPID0–6 (P < 0.001) and for total pain relief (P < 0.001). There were no significant differences between aspirin and acetaminophen with codeine at any evaluation of SPID (P ≥ 0.070), complete relief (P ≥ 0.179), or time to meaningful relief (P ≥ 0.245). Regarding safety, there were no statistically significant differences between treatment groups in the incidence of adverse events in the dental pain and tension-type headache studies. ConclusionsThese 2 randomized, double-blind, placebo-controlled studies demonstrate that treatment with aspirin (1000 mg) provides statistically significant analgesic efficacy compared with placebo use and comparable efficacy with acetaminophen (300 mg) with codeine (30 mg) therapy after impacted third molar extraction and in tension- type headache.

Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: A phase I, open-label, single-dose clinical trial

Background: Aclidinium bromide is an inhaled, long-acting muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease. Renal impairment may affect drug clearance. Objective: This study was conducted to evaluate the pharmacokinetic (PK) parameters, safety, and tolerability of aclidinium bromide and its metabolites in patients with normal and impaired renal function to determine whether dosing adjustments are required when renal dysfunction is present. Methods: This was a Phase I, open-label, single-center, single-dose clinical trial conducted in Munich, Germany. Adults with varying degrees of renal function were assigned to 4 groups (n = 6 for each) based on creatinine clearance, including normal renal function (>80 mL/ min), mild renal insufficiency (>50-⪯80 mL/min), moderate renal insufficiency (>30-⪯50 mL/min), and severe renal insufficiency (<30 mL/min). Single doses of aclidinium bromide 400 μg were administered using a multidose dry powder inhaler. Blood and urine samples were obtained before dosing and at various time points up to 48 hours after dosing to analyze the PK parameters of aclidinium bromide and its metabolites. Plasma PK Parameters were AUC 0-t, MJC 0-∞ C max, T max, t ½ CL/F and apparent volume of distribution during the terminal phase Xz; urinary parameters were the amount of aclidinium or acid or alcohol metabolite excreted in urine, the percentage of the dose excreted in urine (fe), and renal clearance (CL R). Tolerability was assessed using physical examination, vital signs, 12-lead ECG recordings, laboratory tests, and adverse-event (AE) reports. The Wilcoxon rank sum test was used to compare the median PK values between the normal and impaired renal function groups. Pearson correlation coefficients and linear regression models were used to analyze the relationship between creatinine clearance and AUC 0-∞ and between creatinine clearance and CL R for aclidinium and its metabolites. Results: A total of 16 men and 8 women were included in the study. All participants were white; mean (SD) age was 55 (10.7) years and weight was 70.8 (9.2) kg. Aclidinium Cmax was observed in plasma by 5 minutes after dosing (ie, median Tmax) and did not differ significantly among the renal function groups. Plasma concentrations of aclidinium declined after reaching Cmax, with median t ½ values ranging from 2.07 to 4.18 hours across all renal function groups. Most of the individual t ½ values were between 1.5 and 3.5 hours, regardless of the degree of renal insufficiency. No significant relationship between AUC 0-∞) and creatinine clearance was observed (Pearson correlation coefficient = −0.0446; P = NS). Urinary excretion of aclidinium was very low, with a mean 0.090% (median 0.078%) of the dose recovered from the urine in participants with normal renal function. Eight AEs were reported in 7 participants after drug administration; all were mild to moderate in severity and resolved spontaneously. There were no serious drug-related AEs and no deaths. Conclusions: The plasma PK parameters of aclidinium bromide were not significantly altered after a single inhaled dose of aclidinium bromide 400 μg in this small group of patients with various degrees of impaired renal function. The very low urinary excretion of aclidinium in all renal function groups indicates that renal function plays a minor role in aclidinium plasma clearance. Aclidinium appeared well tolerated in the population studied. These results suggest that aclidinium dose adjustment on the basis of renal function may not be necessary.

Dyloject®, a novel injectable diclofenac solubilised with cyclodextrin: Reduced incidence of thrombophlebitis compared to injectable diclofenac solubilised with polyethylene glycol and benzyl alcohol

Summary Background Thrombophlebitis is a common complication of a widely used formulation of injectable diclofenac that employs propylene glycol and benzyl alcohol (PG–BA) as solvents. Initial studies of Dyloject®, a novel injectable diclofenac solubilised with hydroxypropyl-β-cyclodextrin (HPβCD), suggested that this complication occurred less frequently and with lower severity with the newer formulation. Methods We conducted a safety analysis of seven single-dose clinical trials that enrolled 531 patients receiving either a rapid intravenous (IV) bolus of Dyloject® or a 30 min IV infusion of PG–BA diclofenac. Results The incidence of thrombophlebitis observed as an adverse event following Dyloject® treatment was 1.2% (5 of 423) versus 6.5% (7 of 108) following PG–BA diclofenac (p Conclusion HPβCD, the solubilising agent in Dyloject®, may be less irritating and result in less clinical thrombophlebitis than the cosolvents propylene glycol and benzyl alcohol used in PG–BA diclofenac.

Effect of food intake on the bioavailability of almotriptan, an antimigraine compound, in healthy volunteers: an open, randomized, crossover, single-dose clinical trial

This open, randomized, crossover, single-dose clinical trial evaluated the possible pharmacokinetic interaction between a single oral dose of almotriptan 25 mg, a 5-HT1B/1D receptor agonist for the acute treatment of migraine, and food intake in healthy volunteers. The influence of food intake in the rate and extent of almotriptan absorption was evaluated by bioequivalence criteria. Tolerability and safety of treatment were also assessed. 16 healthy volunteers (8 men and 8 women, aged 19-27 years) received a crossed single oral dose of almotriptan 25 mg under fasting and fed conditions, separated by a 7-day washout period. The treatment given under fasting condition was considered as reference. Plasma levels of almotriptan were analyzed using high-performance liquid chromatography (HPLC) and UV detection at 227 nm. The 90% confidence intervals (CI) for the logarithmically transformed Cmax and AUC0-infinity, values of almotriptan under fasting and fed conditions (97.8 - 124% and 102.9 - 108.2%, respectively) fell into the predetermined accepted range of 80 - 125%. No statistically significant differences in Cmax, tmax, AUC0-infinity, MRT and t1/2 were observed under fasting and fed conditions between men and women. Tolerability of treatments was good throughout the whole study period. In conclusion, administration of almotriptan 25 mg is bioequivalent under fasting and fed conditions in healthy men and women. Therefore, it is unlikely that concomitant food intake would produce clinially relevant differences in therapeutic effect with almotriptan at the dose studied here.

Outcomes in acute pain trials: systematic review of what was reported?

Single-dose clinical trial methods for evaluating analgesics have been used successfully for over 50 years. The aims of this review were to examine which pain measurement scales have been used in high quality acute pain trials, to investigate other common measurements or characteristics, to confirm that different scales used by standard methods give the same estimate of analgesic effect, to investigate remedication methodologies and the potential of ‘time to remedication’ as a standard outcome. Published reports of randomised, double blind, placebo-controlled trials, investigating at least 20 adult patients (10 patients per treatment arm) experiencing moderate or severe pain using at least one standard pain intensity or pain relief scale were sought. Key design features, outputs and outcomes were catalogued for each report. The main outcomes reported were misleading, detailing only the mean values of data with a demonstrably skewed distribution. After 50 years, the reporting of results from acute pain trials warrants a fresh look. Possible improvements include reporting the number of patients with certain levels of pain relief, or the actual number (percentage) of patients with a certain level of pain relief at a certain time, or more useful information on remedication from trials of at least 12 h duration. Most useful would be all three. Further exploration would only be possible from analysis at the individual patient level.