Dosing Occasions Research Articles

Safety and pharmacokinetic properties of a new formulation of parenteral artesunate in healthy Thai volunteers

BackgroundParenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers.MethodsThis was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration–time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation.ResultsBoth intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation.ConclusionsThe new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects.Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002).

Model-Informed Precision Dosing to Reduce Vincristine-Induced Peripheral Neuropathy in Pediatric Patients: A Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis.

Vincristine-induced peripheral neuropathy (VIPN) is a common adverse effect of vincristine, a drug often used in pediatric oncology. Previous studies demonstrated large inter- and intrapatient variability in vincristine pharmacokinetics (PK). Model-informed precision dosing (MIPD) can be applied to calculate patient exposure and individualize dosing using therapeutic drug monitoring (TDM) measurements. This study set out to investigate the PK/pharmacodynamic (PKPD) relationship of VIPN and determine the utility of MIPD to support clinical decisions regarding dose selection and individualization. Data from 35 pediatric patients were utilized to quantify the relationship between vincristine dose, exposure and the development of VIPN. Measurements of vincristine exposure and VIPN (Common Terminology Criteria for Adverse Events [CTCAE]) were available at baseline and for each subsequent dosing occasions (1-5). A PK and PKPD analysis was performed to assess the inter- and intraindividual variability in vincristine exposure and VIPN over time. In silico trials were performed to portray the utility of vincristine MIPD in pediatric subpopulations with a certain age, weight and cytochrome P450 (CYP)3A5 genotype distribution. A two-compartmental model with linear PK provided a good description of the vincristine exposure data. Clearance and distribution parameters were related to bodyweight through allometric scaling. A proportional odds model with Markovian elements described the incidence of Grades 0, 1 and ≥2 VIPN overdosing occasions. Vincristine area under the curve (AUC) was the most significant exposure metric related to the development of VIPN, where an AUC of 50 ng⋅h/mL was estimated to be related to an average VIPN probability of 40% over five dosing occasions. The incidence of Grade ≥2 VIPN reduced from 62.1 to 53.9% for MIPD-based dosing compared with body surface area (BSA)-based dosing in patients. Dose decreases occurred in 81.4% of patients with MIPD (vs. 86.4% for standard dosing) and dose increments were performed in 33.4% of patients (no dose increments allowed for standard dosing). The PK and PKPD analysis supports the use of MIPD to guide clinical dose decisions and reduce the incidence of VIPN. The current work can be used to support decisions with respect to dose selection and dose individualization in children receiving vincristine.

594. An Open-Label Study in Healthy Volunteers to Determine the Absolute Bioavailability of, the Effect of Food and Dosing by Nasogastric Tube upon the Pharmacokinetics of a Single Oral Dose of Olorofim (OLO)

Abstract Background OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. Information on absolute bioavailability and effect of food upon the pharmacokinetics (PK) of OLO when administered as a 30 mg tablet, including feasibility of alternative enteral delivery, is required for appropriate guidance on dosing. Methods Healthy male and female subjects in Cohorts A and B (6/cohort; high carbohydrate /low fat meals at 8 and 24 h for Cohort A and low carbohydrate/high fat meals for Cohort B ) participated in 3 treatment periods; single doses of 150 mg OLO as a 2-h IV infusion, a fasted PO dose (after overnight fast), and a fed single PO dose (30 min after starting a high fat breakfast). Healthy subjects in Cohort C participated in 2 treatment periods and received fasted single doses of 150 mg OLO either PO as intact tablets or via NG tube (tablets dispersed in water). PK sampling was performed for 120 h after each dose, with at least 10 days between dosing occasions per subject. Results The absolute bioavailability of a fasted single PO dose of OLO was found to be 67%. Administering OLO in the presence of food resulted in slight reduction in overall exposure, with an approximate 30% reduction in Cmax (Table 1). Multiple post-dose OLO peaks were observed for most subjects regardless of dose route or fed state; peaks typically coincided with meal times (Figure). OLO systemic exposure was similar for intact tablets given PO and tablets dispersed in water given via NG tube (Table). Statistical Analysis of Olorofim PK parameters for Cohorts A, B and C Conclusion OLO (30 mg tablet) has good oral bioavailability and based upon the minimal impact of a high-fat breakfast upon overall exposure, can be administered with or without food. No dose adjustment is needed if switching from oral dosing with intact tablets to dosing tablet in water via NG tube. Disclosures Karen Cornelissen, PhD, F2G: Employee Paul A. Newell, MB BS, AstraZeneca: Stocks/Bonds|F2G: Stocks/Bonds John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Samuel Israel, MBBS, Labcorp: Eemployee James Bush, MB ChB, PhD, Labcorp: Employee (Salaried)|Labcorp: Stocks/Bonds.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.

Dosing for Personalized Prophylaxis in Hemophilia A Highly Varies on the Underlying Population Pharmacokinetic Models.

Model-informed personalized prophylaxis with factor VIII (FVIII) replacement therapy aimed at higher trough levels is becoming indispensable for patients with severe hemophilia A. This study aimed to identify the most suitable population pharmacokinetic (PK) models for personalized prophylaxis using various FVIII products and 2 clinical assays and to implement the most suitable one in open-access software. Twelve published population PK models were systematically compared to predict the time above target (TaT) for a reference dosing occasion. External validation was performed using a 5-point PK data from 39 adult patients with hemophilia A with FVIII measured by chromogenic substrate (CSA) and 1-stage assays (OSAs) using NONMEM under 3 different conditions: a priori (with all FVIII samples blinded), a posteriori (with 1 trough sample), and general model fit (with all FVIII samples including the reference dosing occasion provided). On average, the baseline covariate models overpredicted TaT (a priori; bias -3.8 hours to 49.6 hours). When additionally including 1 previous trough FVIII sample before the reference dosing occasion (a posteriori), only 50% of the models improved in bias (-1.0 hours to 36.5 hours) and imprecision (22.4 hours and 60.7 hours). Using all the time points (general model fit), the models accurately predicted (individual TaT less than ±12 hours compared with the reference) 62%-90% and 33%-74% of the patients using CSA and OSA data, respectively. Across all scenarios, predictions using CSA data were more accurate than those using the OSA data. One model performed best across the population (bias: -3.8 hours a priori, -1.0 hours a posteriori , and 0.6 hours general model fit ) and acceptably predicted 44% (a priori) to 90% ( general model fit ) of the patients. To allow the community-based evaluation of patient-individual FVIII dosing, this model was implemented in the open-access model-informed precision dosing software "TDMx."

Evaluation of published population pharmacokinetic models to inform tacrolimus dosing in adult heart transplant recipients.

Identification of the most appropriate population pharmacokinetic model-based Bayesian estimation is required prior to its implementation in routine clinical practice to inform tacrolimus dosing decisions. This study aimed to determine the predictive performances of relevant population pharmacokinetic models of tacrolimus developed from various solid organ transplant recipient populations in adult heart transplant recipients, stratified based on concomitant azole antifungal use. Concomitant azole antifungal therapy alters tacrolimus pharmacokinetics substantially, necessitating dose adjustments. Population pharmacokinetic models of tacrolimus were selected (n =17) for evaluation from a recent systematic review. The models were transcribed and implemented in NONMEM version 7.4.3. Data from 85 heart transplant recipients (2387 tacrolimus concentrations) administered the oral immediate-release formulation of tacrolimus (Prograf) were obtained up to 391 days post-transplant. The performance of each model was evaluated using: (i) prediction-based assessment (bias and imprecision) of the individual predicted tacrolimus concentration of the fourth dosing occasion (MAXEVAL = 0, FOCE-I) from 1-3 prior dosing occasions; and (ii) simulation-based assessment (prediction-corrected visual predictive check). Both assessments were stratified based on concomitant azole antifungal use. Regardless of the number of prior dosing occasions (1-3) and concomitant azole antifungal use, all models demonstrated unacceptable individual predicted tacrolimus concentration of the fourth dosing occasion (n =152). The prediction-corrected visual predictive check graphics indicated that these models inadequately predicted observed tacrolimus concentrations. All models evaluated were unable to adequately describe tacrolimus pharmacokinetics in adult heart transplant recipients included in this study. Further work is required to describe tacrolimus pharmacokinetics for our heart transplant recipient cohort.

025 Population Pharmacokinetic Modeling and Simulation to Assess the Impact of an 8 Week Maintenance Dosing Regimen for Intramuscular Testosterone Undecanoate

Intramuscular testosterone undecanoate is indicated for testosterone replacement in adult males with a deficiency or absence of endogenous testosterone. Intramuscular testosterone undecanoate is currently approved to be administered at initiation and at 4 weeks followed by a maintenance dose every 10 weeks (750 mg on each dosing occasion). However, a more frequent maintenance regimen (every 8 weeks) may improve the management of symptoms of low testosterone at the end of each dosing interval.

Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke ) was 0.09 (SD, 0.04) h-1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h-1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h-1 A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

P031 Systematic-analysis of injection-site pain from administration of subcutaneous adalimumab biosimilar FKB327 versus the adalimumab reference product humira via different methods

BACKGROUND: FKB327 is a proposed biosimilar of the adalimumab reference product (RP). Several studies in both healthy volunteers and patients with active rheumatoid arthritis (RA) were undertaken, the results of which have been reported elsewhere. The formulation excipients of the biosimilar product differ from that of the RP, and different injection-site pain with subcutaneous injection has been reported. The current meta-analysis examines pooled data from these studies in relation to the amount of injection-site pain resulting from using prefilled syringes (PFS) versus auto-injectors (AI) versus regular syringes (RS) and the proposed biosimilar, FKB327, versus the RP. METHODS: Data from 4 studies, FKB327-001, -002, -003, and -004, were pooled in an effort to compare injection-site pain upon subcutaneous administration of FKB327 versus the RP (citrate-containing formulation of the RP (40 mg/0.8 mL). Study FKB327-001, in healthy volunteers (n = 180), involved a single subcutaneous dose of either FKB327 or the RP. Study FKB327-004 was a similar study in healthy Japanese volunteers (n = 130). Study FKB327-002 was a randomized (FKB327 with RS or the RP), double-blind, multiple-dose study in patients with active RA. This was followed by Study FKB327-003, in which patients were rerandomized to receive either FKB327-PFS or the RP in the randomization phase, followed by an open-label extension phase of the study, in which AI was introduced. As patients were continued on treatment or switched during the course of the FKB327-002 and -003 studies, the injection-site pain was assessed at the first dosing occasion of FKB327 or the RP (n = 691). Data from all 4 studies were examined by meta-analysis of the visual analog scale (VAS) using a 100-mm horizontal scale for FKB327 versus the RP and for comparison of AI, PFS, and RS. RESULTS: Data were analyzed from a total of 2007 assessments in 1,001 subjects. A linear mixed model of the VAS in mm for the RP versus FKB327 across all 4 studies showed a 12.6-point improvement in the score for FKB327 versus the RP (95% confidence interval [CI], –14.3 to –10.8; P &lt; 0.001). For the AI and PFS used for FKB327 administration, AI showed a 1.7-point improvement in VAS compared with PFS (95% CI, –3.3 to –0.1; P = 0.035). Gender, age, body weight, and population (healthy subject or patient) were not identified for differences in injection-site pain. CONCLUSION(S): FKB327 showed a significant advantage in terms of injection-site pain compared with the RP, as well as lack of inferiority for both AI and PFS versus RS.

Towards precision dosing of vancomycin: a systematic evaluation of pharmacometric models for Bayesian forecasting

ObjectivesVancomycin is a vital treatment option for patients suffering from critical infections, and therapeutic drug monitoring is recommended. Bayesian forecasting is reported to improve trough concentration monitoring for dose adjustment. However, the predictive performance of pharmacokinetic models that are utilized for Bayesian forecasting has not been systematically evaluated. MethodThirty-one published population pharmacokinetic models for vancomycin were encoded in NONMEM®7.4. Data from 292 hospitalized patients were used to evaluate the predictive performance (forecasting bias and precision, visual predictive checks) of the models to forecast vancomycin concentrations and area under the curve (AUC) by (a) a priori prediction, i.e., solely by patient characteristics, and (b) also including measured vancomycin concentrations from previous dosing occasions using Bayesian forecasting. ResultsA priori prediction varied substantially—relative bias (rBias): –122.7–67.96%, relative root mean squared error (rRMSE) 44.3–136.8%, respectively—and was best for models which included body weight and creatinine clearance as covariates. The model by Goti et al. displayed the best predictive performance with an rBias of –4.41% and an rRMSE of 44.3%, as well as the most accurate visual predictive checks and AUC predictions. Models with less accurate predictive performance provided distorted AUC predictions which may lead to inappropriate dosing decisions. ConclusionThere is a diverse landscape of population pharmacokinetic models for vancomycin with varied predictive performance in Bayesian forecasting. Our study revealed the Goti model as suitable for improving precision dosing in hospitalized patients. Therefore, it should be used to drive vancomycin dosing decisions, and studies to link this finding to clinical outcomes are warranted.

Hypersensitivity incidence after sugammadex administration in healthy subjects: a randomised controlled trial

BackgroundWe evaluated the incidence of hypersensitivity or anaphylaxis after repeated single-dose sugammadex administration in non-anaesthetised adults. MethodsIn this multicentre, double-blind study (NCT02028065), healthy volunteer subjects were randomised (2:2:1 ratio) to one of three groups to receive three repeated intravenous injections of sugammadex 4 or 16 mg kg−1, or placebo, separated by a ∼5 week intervals. Targeted hypersensitivity assessments were performed 0.5, 4, and 24 h post-dosing, and hypersensitivity signs/symptoms were referred to a blinded independent Adjudication Committee. Anaphylaxis was determined per Sampson (Criterion 1). The primary endpoint was the proportion with confirmed hypersensitivity. ResultsOf 375 evaluable subjects, 25 had confirmed hypersensitivity [sugammadex 4 mg kg−1: 10/151 (6.6%); sugammadex 16 mg kg−1: 14/148 (9.5%); placebo: 1/76 (1.3%)]. The differences in incidence rates vs placebo were 5.3% (95% confidence interval: –0.9, 10.7) for sugammadex 4 mg kg−1 and 8.1% (1.7, 14.2) for 16 mg kg−1. Incidence was similar across sugammadex doses and dosing occasions, including in subjects with reactions to previous doses. Three subjects (16 mg kg−1 group) required antihistamines/corticosteroids and discontinued the study, per protocol; symptoms resolved and no subject required epinephrine. One subject with anaphylaxis after the first 16 mg kg−1 dose recovered completely post-treatment. There were no clinically relevant anti-sugammadex antibody or tryptase findings. ConclusionsHypersensitivity in response to sugammadex administration can occur in healthy subjects without history of previous sugammadex exposure. Hypersensitivity incidence was similar across sugammadex doses and numerically higher than placebo, with no evidence of sensitisation with repeated administration. Hypersensitivity is unlikely to be mediated through sugammadex-specific immunoglobulin G- or E-mediated mast cell stimulation in healthy volunteers. Clinical trial registrationNCT02028065.

Actual use of and adherence to ibuprofen 400mg tablet dosing instructions in a simulated OTC environment .

Evaluate adherence of US consumers to proposed label directions for a new 400 mg ibuprofen formulation. In this single-arm, open-label, multicenter, 30-day study simulating an over-the-counter (OTC)-like environment, US analgesic consumers reviewed proposed product packaging for a new 400 mg ibuprofen formulation and made a purchase decision. Purchasers used the product as needed and recorded use over 30 days. Outcomes included the percentage of participants who exhibited correct or acceptable product use for the primary endpoint (not exceeding 1,200mg/day >2 times during the study) or secondary endpoint (not exceeding 400mg/dose >2 times during the study) and adherence to the labeled dosing interval of 6-8 hours. Primary endpoint success was met if the lower bound of the 95% confidence interval (CI) was ≥85%. Of 685 purchasers providing use data, correct or acceptable use behavior occurred in 95.2% (95% CI: 93.6%, 96.8%) regarding total daily dose and in 84.4% (95% CI: 81.7%, 87.1%) regarding the number of tablets taken per dosing occasion. Most participants (87.3%) never used >1,200 mg/day or took >1 tablet/dose (78.1%). Nearly 43% of subjects re-dosed within 6hours of the previous dose; of these, ~82% re-dosed between the 4- and 6-hour time intervals. Adverse events were consistent with prior ibuprofen 200mg experience. This study provides evidence that a majority of US consumers would be able to use OTC ibuprofen 400mg tablets in a manner consistent with product labeling. Misuse rates were low and unlikely to generate an excess risk of clinically important adverse events. .

Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.

BackgroundArtemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine.Methods and FindingsPublished pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration–time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers’ currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3–44.3) ng/ml in small children compared to 38.1 (25.8–56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%–32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413–0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers’ recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals.ConclusionsThe derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015).

Quantifying the Effectiveness of Dose Individualization by Simulation for a Drug With Moderate Pharmacokinetic Variability.

Dose individualization can reduce variability in exposure. The objective of this work was to quantify, through pharmacokinetic (PK) simulation, the potential for reducing the variability in exposure by dose individualization for a drug with moderate PK variability between subjects and between occasions within a subject, and a narrow therapeutic window. Using a population PK model that includes between-subject and between-occasion variability for apparent clearance, individual PK profiles in a trial of 300 subjects after a test dose were simulated. From the simulated data, datasets were created mimicking various sampling regimens (from single predose sample to full profile samples over 12 hours) on 1 or more occasions (1, 2, 3, 5, or 10 visits). Using these datasets, individual apparent clearance values were estimated, which were then used to calculate an individualized dose for a predefined target area under the concentration-time curve (AUC), based on the available formulation strengths. The proportion of people whose mean AUC was within a predefined therapeutic AUC range was calculated for the test (before) and the individualized dose (after), and compared between the different sampling scenarios. The maximum increase in proportion of subjects with an AUC within the range was 20%. To achieve this benefit, PK samples over 4 hours from 100 dosing occasions were required. As a result of the dose adjustment, the AUC of 7.3% of the subjects moved from inside the therapeutic range to outside of the range. This work shows how modeling and simulation can help assess the benefit and risk of dose individualization for a compound with variability between subjects and between occasions. The framework can be applied to similar situations with a defined set of conditions (eg, therapeutic window, tablet strengths, and PK and/or pharmacodynamic sampling scheme) to inform dose change and to assess the utility of dose individualization against certain success criteria.

Potential drug-related problems detected by electronic expert support system: physicians' views on clinical relevance.

Drug-related problems cause suffering for patients and substantial costs. Multi-dose drug dispensing is a service in which patients receive their medication packed in bags with one unit for each dose occasion. The electronic expert support system (EES) is a clinical decision support system that provides alerts if potential drug-related problems are detected among a patients' current prescriptions, including drug-drug interactions, therapy duplications, high doses, drug-disease interactions, drug gender warnings, and inappropriate drugs and doses for geriatric or pediatric patients. The aim of the study was to explore physicians' views on the clinical relevance of alerts provided by EES. Furthermore we investigated if physicians performed any changes in drug treatment following the alerts and if there were any differences in perceived relevance and performed changes between different types of alerts and drugs. Two geriatric clinics and three primary care units in Sweden. Prescribed medications for patients (n = 254) with multi-dose drug dispensing were analyzed for potential drug-related problems using EES. For each alert, a physician assessed clinical relevance and indicated any intended action. A total of 15 physicians took part in the study. Changes in drug treatment following the alerts were later measured. The relationship between variables was analyzed using Chi square test. Physicians' perceived clinical relevance of each alert, and changes in drug treatment following the alerts. Physicians perceived 68% (502/740) of EES alerts as clinically relevant and 11% of all alerts were followed by a change in drug treatment. Clinical relevance and likelihood to make changes in drug treatment was related to the alert category and substances involved in the alert. In most patients with multi-dose drug dispensing, EES detected potential drug-related problems, with the majority of the alerts regarded as clinically relevant and some followed by measurable changes in drug treatment.

The absolute bioavailability of racemic ketamine from a novel sublingual formulation.

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability. The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales. The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability. Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.

Population pharmacokinetic assessment of the effect of food on piperaquine bioavailability in patients with uncomplicated malaria.

Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with (n = 15) and without (n = 15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.

A Novel Double-Tracer Technique to Characterize Absorption, Distribution, Metabolism and Excretion (ADME) of [14C]Tofogliflozin After Oral Administration and Concomitant Intravenous Microdose Administration of [13C]Tofogliflozin in Humans

Human mass balance studies and the assessment of absolute oral bioavailability (F) are usually assessed in separate studies. Intravenous microdose administration of an isotope tracer concomitant to an unlabeled oral dose is an emerging technique to assess F. We report a novel double-tracer approach implemented for tofogliflozin combining oral administration of a radiolabel tracer with concomitant intravenous administration of a stable isotope tracer. Tofogliflozin is a potent and selective sodium/glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus currently in clinical development. The objectives of the present study were to assess the systemic exposure of major circulating metabolites, excretion balance, F and contribution of renal clearance (CLR) to total clearance (CL) of tofogliflozin in healthy subjects within one study applying a novel double-tracer technique. Six healthy male subjects received 20 mg [(12)C/(14)C]tofogliflozin (3.73 MBq) orally and a concomitant microdose of 0.1 mg [(13)C]tofogliflozin intravenously. Pharmacokinetics of tofogliflozin were determined for the oral and intravenous route; the pharmacokinetics of the metabolites M1 and M5 were determined for the oral route. Quantification of [(12)C]tofogliflozin in plasma and urine and [(13)C]tofogliflozin in plasma was performed by selective LC-MS/MS methods. For the pre-selected metabolites of tofogliflozin, M1 and M5, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to plasma and urine samples. Total radioactivity was assessed in plasma, urine and feces. Pharmacokinetic analysis was conducted by non-compartmental methods. The pharmacokinetics of tofogliflozin in healthy subjects were characterized by an F of 97.5 ± 12.3 %, CL of 10.0 ± 1.3 l/h and volume of distribution at steady-state (V(ss)) of 50.6 ± 6.7 l. The main route of elimination of total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose). The observed CL(R) of 25.7 ± 5.0 ml/min was higher than the product of the estimated glomerular filtration rate (eGFR) and fraction unbound in plasma (f(u)) (eGFR × f(u) 15 ml/min), indicating the presence of net active tubular secretion in the renal elimination of tofogliflozin. However, CLR contributed only 15.5 % to the CL of tofogliflozin, suggesting that reductions in CLR by renal impairment won't significantly affect systemic exposure to tofogliflozin. Tofogliflozin and its metabolite M1 were the only major circulating entities accounting for 46 ± 8.6 and 50 ± 8.2 %, respectively, of total circulating drug-related material, while the metabolite M5 was a minor circulating metabolite accounting for 3.0 ± 0.3 % of total circulating drug-related material. Both the M1 and M5 metabolites were excreted into urine and the major metabolite M1 did not exhibit active tubular secretion. These results demonstrate the utility of the double-tracer approach to provide essential pharmacokinetic data and excretion data for drug-related material in one study at the same dosing occasion. The data obtained allowed the characterization of absorption, distribution, metabolism and excretion of tofogliflozin. Tofogliflozin exhibited highly favorable pharmacokinetic properties as demonstrated by its high F, low CL and a low V(ss. The presence of only one major circulating metabolite of tofogliflozin was unambiguously demonstrated. As a drug targeting the kidney, luminal exposure of the kidney is achieved by renal filtration and active tubular secretion.

Topical Treatment with the Toll-like Receptor Agonist DIMS0150 Has Potential for Lasting Relief of Symptoms in Patients with Chronic Active Ulcerative Colitis by Restoring Glucocorticoid Sensitivity

Patients with chronic active ulcerative colitis (UC) are regarded as treatment failures and represent an area of high unmet medical need, as normally the only remaining option is colectomy. We treated a total of eight chronic active severe UC outpatients with the immunomodulatory agent DIMS0150 as an add-on to current therapies. Seven patients received a single topical dose of 30 mg and one special case subject received three doses with 4 weeks between dosing occasions. All patients were classed as treatment failures and were elected for colectomy. Efficacy evaluation was determined in terms of colitis activity index, endoscopic improvement, and histologic disease activity assessed primarily at week 12 with a follow-up period of over 2 years. Glucocorticoid sensitivity was assayed by in vitro measurement of interleukin 6. All patients demonstrated a pronounced and rapid reduction in their colitis activity index within 1 week following a single intracolonic administration via colonoscope of the agent DIMS0150. Further improvements were evident at week 4, resulting in a clinical response rate for the single-dose treatment of 71%, with 43% in clinical remission. By week 12 the clinical response and remission rates had reached 82% and 71%, respectively. A follow-up period of over 2 years posttreatment indicated that all but one of the treated patients had avoided the need for colectomy, with the longest patient being in symptom-free remission for over 27 months. Treatment with DIMS0150 restored glucocorticoid sensitivity. DIMS0150 may have the potential to be an effective agent to treat chronic active UC patients with the prospect to avoid colectomy on a long-term basis and is currently the subject of a clinical phase III study (EudraCT number: 2011-003130-14).

Association between Multi-Dose Drug Dispensing and Quality of Drug Treatment – A Register-Based Study

BackgroundIn the elderly in Scandinavia, multi-dose drug dispensing (MDD) is a common alternative to ordinary prescriptions (OP). MDD patients receive their drugs in unit bags, one for each dose occasion. The prescribing procedure differs between MDD and OP. The aim of the present study was to investigate the association between MDD and quality of drug treatment (QDT).Methodology/Principal FindingsA cross-sectional study was performed of all inhabitants in Region Västra Götaland alive on December 31st 2007, aged ≥65 years, with ≥1 prescribed drug and ≥2 health care visits for ≥2 diagnoses for obstructive pulmonary disease, diabetes mellitus, and/or cardiovascular disease in 2005–2007 (n = 24,146). For each patient, drug treatment on December 31st 2007 was estimated from drugs registered in the Swedish Prescribed Drug Register. QDT was evaluated according to established quality indicators (≥10 drugs, Long-acting benzodiazepines, Drugs with anticholinergic action, ≥3 psychotropics, and Drugs combinations that should be avoided). Logistic regression, with adjustments for age, sex, burden of disease, and residence, was performed to investigate the association between MDD and QDT. Mean age was 77 years, 51% were females, and 20% used MDD. For all quality indicators, the proportion of patients with poor QDT was greater in patients with MDD than in patients with OP (all P<0.0001). Unadjusted and adjusted odds ratios (95% confidence intervals) for poor QDT (MDD patients vs. OP patients) ranged from 1.47 (1.30–1.65) to 7.08 (6.30–7.96) and from 1.36 (1.18–1.57) to 5.48 (4.76–6.30), respectively.Conclusions/SignificancePatients with MDD have poorer QDT than patients with OP. This cannot be explained by differences in age, sex, burden of disease, or residence. These findings must be taken into account when designing alternative prescribing systems. Further research is needed to evaluate causative factors and if the findings also apply to other dose dispensing systems.