Pharmacokinetic and Pharmacodynamic Analysis of Acetaminophen and Ibuprofen Dual Therapy for Patent Ductus Arteriosus Closure in Preterm Neonates at Less Than 29 Weeks of Gestation.

Patent ductus arteriosus (PDA) is a blood vessel that critically supports fetal circulation. The ductus naturally closes within a few days after birth. However, it can stay open in premature neonates for an extended period of time, which is associated with increased mortality and various co-morbidities. Ibuprofen and indomethacin are currently the only 2 drugs approved for inducing PDA closure, but both have been associated with adverse renal and bleeding events. Clinical evidence suggests that combining acetaminophen (APAP) and ibuprofen treatments can decrease the need for surgical ligation. The objective of this study was to establish a disease-drug-trial model to characterize and predict PDA closure following single and combination drug therapy with ibuprofen and/or APAP in children at less than 29 weeks of gestation. The model was informed by a comprehensive literature review. The results of our analysis suggest that ibuprofen and APAP achieve therapeutic synergy. They further suggest that the younger the preterm neonates, the higher the treatment benefit. A 5-day oral dosing regimen consisting of ibuprofen (20 mg/kg Q24h on day 1, followed by 10 mg/kg Q24h on days 2-5) plus APAP (15 mg/kg Q6h) was deemed appropriate to achieve at least 90% PDA in all preterm neonates evaluated within 1 month of life. The model can now be used to design prospective pediatric trials to evaluate optimal drug combinations for PDA closure in preterm neonates and to refine optimal dosing regimens in cohorts of differing gestational age.

Comprehensive Physiologically Based Pharmacokinetic Model to Assess Drug-Drug Interactions of Phenytoin.

Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug's safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus® to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.

Combination Therapy to Kill Mycobacterium tuberculosis in Its Nonreplicating Persister Phenotype.

Mycobacterium tuberculosis (Mtb) exists in various metabolic states, including a nonreplicating persister (NRP) phenotype which may affect response to therapy. We have adopted a model-informed strategy to accelerate discovery of effective Mtb treatment regimens and previously found pretomanid (PMD), moxifloxacin (MXF), and bedaquiline (BDQ) to readily kill logarithmic- and acid-phase Mtb. Here, we studied multiple concentrations of each drug in flask-based, time-kill studies against NRP Mtb in single-, two- and three-drug combinations, including the active M2 metabolite of BDQ. We used nonparametric population algorithms in the Pmetrics package for R to model the data and to simulate the 95% confidence interval of bacterial population decline due to the two-drug combination regimen of PMD + MXF and compared this to observed declines with three-drug regimens. PMD + MXF at concentrations equivalent to average or peak human concentrations effectively eradicated Mtb. Unlike other states for Mtb, we observed no sustained emergence of less susceptible isolates for any regimen. The addition of BDQ as a third drug significantly (P < 0.05) shortened time to total bacterial suppression by 3 days compared to the two-drug regimen, similar to our findings for Mtb in logarithmic or acid growth phases.

Evaluating the effect of clofazimine against Mycobacterium tuberculosis given alone or in combination with pretomanid, bedaquiline or linezolid.

In recent years, clofazimine (CFZ) has been regaining prominence for the treatment of tuberculosis. However, it shows limited efficacy as a single drug and optimal combination partners have not been identified. Therefore, the objective of our analysis was to evaluate the efficacy of CFZ-containing two-drug regimens with pretomanid (PMD), bedaquiline (BDQ) or linezolid (LZD) by: (i) determining their pharmacodynamic (PD) mode of interaction against Mycobacterium tuberculosis (Mtb) strain H37Rv in log- phase and acid-phase metabolic states, and against Mtb strain 18b in a non-replicating persister (NRP) metabolic state; (ii) predicting bacterial cell kill of the drugs alone and in combination; and (iii) evaluating the relationship between the interaction mode and the extent of bacterial cell kill. The results of our Greco universal response surface analysis showed that CFZ was at least additive with a clear trend towards synergy when combined with PMD, BDQ and LZD against Mtb in all explored metabolic states under in vitro checkerboard assay conditions. The results further showed that all two-drug combination regimens exerted greater bacterial kill than any of the drugs alone. CFZ alone showed the least antimicrobial efficacy amongst the evaluated drugs, and there was a lack of correlation between the mode of interaction and the extent of bacterial kill. However, we may underestimate the effect of CFZ in this screening approach owing to limited in vitro study duration and neglect of target site accumulation. Clofazimine; Pretomanid; Bedaquiline; Linezolid; Combination chemotherapy; Mycobacterium tuberculosis.

Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression.

The repurposed agent moxifloxacin has become an important addition to the physician's armamentarium for the therapy of Mycobacterium tuberculosis When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for Mycobacterium tuberculosis therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen. For large populations of patients, there are true between-patient differences in important pharmacokinetic parameters. These distributions of parameter values may have an impact on these metrics, depending on what measure of drug exposure drives the metrics. To optimize dose and schedule choice of moxifloxacin, we performed a dose fractionation experiment in the hollow fiber infection model. We examined 12-, 24-, and 48-h dosing intervals with doses of 200, 400, and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8, and 4 h were simulated. We attempted to keep the average concentration (Cavg) or area under the concentration-time curve (AUC) constant across arms. We found that susceptible bacterial load decline was linked to Cavg, as we had indicated previously. Resistance suppression, a nonmonotonic function, had minimum concentration (Cmin) as the linked index. The 48-h interval with the 4-h half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (linked to peak concentration [Cpeak]), and adherence, we conclude that the dose of 400 mg daily is optimal for moxifloxacin.

The Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy Regimens.

The Mycobacterium tuberculosis drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Single agent therapy is insufficient for patients with late-stage tuberculosis because of resistance emergence. To achieve our therapeutic ends, it is requisite to identify optimal combination regimens. These regimens go through a lengthy and expensive evaluative process. If we have a modest group of 6 to 8 new or repurposed agents, this translates into 15 to 28 possible 2-drug combinations. There is neither time nor resources to give an extensive evaluation for all combinations. We sought a screening procedure that would identify combinations that had a high likelihood of achieving good bacterial burden decline. We examined pretomanid, moxifloxacin, linezolid, and bedaquiline in log-phase growth, acid-phase growth, and nonreplicative persister (NRP) phase in the Greco interaction model. We employed the interaction term α and the calculated bacterial burden decline as metrics to rank different regimens in different metabolic states. No relationship was found between α and bacterial kill. We chose bacterial kill as the prime metric. The combination of pretomanid plus moxifloxacin emerged as the clear frontrunner, as the largest bacterial declines were seen in log phase and acid phase with this regimen and it was second best in NRP phase. Bedaquiline also produced good kill. This screening process may identify optimal combinations that can be further evaluated in both the hollow-fiber infection model and in animal models of Mycobacterium tuberculosis infection.

Knowledge, attitudes & practices of healthcare professionals in hospitals towards the reporting of adverse drug reactions in Saudi Arabia: A multi-centre cross sectional study.

INTRODUCTION: Adverse drug reactions (ADRs) are a major global clinical problem, causing substantial mortality and morbidity especially in hospitals. Healthcare professionals (HCPs) knowledges', attitude and practices are crucial points to evaluate the hospital safety environment. Objective of the study was to investigate the knowledge, attitudes, and practices of HCPs regarding the ADRs reporting system. METHODS: A cross-sectional survey was conducted between January and February of 2013 in nine tertiary care hospitals (governmental and private) that provide highly specialized medical services in Riyadh, Qassim, and the Eastern region of the Kingdom of Saudi Arabia. A validated questionnaire was used to assess the knowledge, attitudes, and practices of HCPs regarding the ADR reporting system. All statistical analyses were performed using SAS version 9.2. RESULTS: In total, 480 questionnaires were distributed, and the response rate was 70% (n = 336). Only 33% of the participants were aware of the National Pharmacovigilance Centre (NPC). Of those HCPs who were familiar with the NPC and their responsibility to report ADRs, most (50%) were pharmacists, followed by physicians (24%) and nurses (16%), and these differences were statistically significant (p < 0.01). Twenty-seven percent of the participants were involved in reporting ADRs; among these HCPs, 62% were pharmacists, 26% were nurses, and 6% were physicians. Most participants (95%) favoured reporting ADRs caused by antibiotics and new/old drugs. The prominent factors discouraging ADR reporting included fear that the report might be incorrect (46%) and lack of time (44%). CONCLUSIONS: A significant lack of knowledge, positive attitudes, and practices regarding ADRs and reporting was observed in hospital HCPs. This finding represents an international concern, and urgent action is needed to promote drug safety and pharmacovigilance in this region.

Pharmacokinetics of tranexamic acid in healthy dogs and assessment of its antifibrinolytic properties in canine blood.

OBJECTIVE To assess pharmacokinetics of tranexamic acid (TXA) in dogs and assess antifibrinolytic properties of TXA in canine blood by use of a thromboelastography-based in vitro model of hyperfibrinolysis. ANIMALS 6 healthy adult dogs. PROCEDURES Dogs received each of 4 TXA treatments (10 mg/kg, IV; 20 mg/kg, IV; approx 15 mg/kg, PO; and approx 20 mg/kg, PO) in a randomized crossover-design study. Blood samples were collected at baseline (time 0; immediately prior to drug administration) and predetermined time points afterward for pharmacokinetic analysis and pharmacodynamic (thromboelastography) analysis by use of an in vitro hyperfibrinolysis model. RESULTS Maximum amplitude (MA [representing maximum clot strength]) significantly increased from baseline at all time points for all treatments. The MA was lower at 360 minutes for the 10-mg/kg IV treatment than for other treatments. Percentage of clot lysis 30 minutes after MA was detected was significantly decreased from baseline at all time points for all treatments; at 360 minutes, this value was higher for the 10-mg/kg IV treatment than for other treatments and higher for the 20-mg/kg IV treatment than for the 20-mg/kg PO treatment. Maximum plasma TXA concentrations were dose dependent. At 20 mg/kg, IV, plasma TXA concentrations briefly exceeded concentrations suggested for complete inhibition of fibrinolysis. Oral drug administration resulted in a later peak antifibrinolytic effect than did IV administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of TXA improved clot strength and decreased fibrinolysis in blood samples from healthy dogs in an in vitro hyperfibrinolysis model. Further research is needed to determine clinical effects of TXA in dogs with hyperfibrinolysis.