Enhancing the local workforce outcomes for rural LICs: what is the role of the local health service in leading innovation in medical education?

INTRODUCTION: It is now 25 years since the Riverland health service began its partnership with Flinders University to create the Parallel Rural Community Curriculum (PRCC) in rural South Australia. What started as a workforce program quickly became a successful disruptive technology for broader pedagogy in medical education. Despite more graduates of the PRCC choosing rural practice compared with their urban rotation-based colleagues, local medical workforce crises have persisted. METHODS: In February 2021, the Local Health Network decided to implement the National Rural Generalist Pathway in its local region. It created the Riverland Academy of Clinical Excellence (RACE) as its vehicle for taking responsibility for training its own health professional workforce. RESULTS: RACE has increased the region's medical workforce by over 20% in 1 year. It gained accreditation as a provider of junior doctor and advanced skills training and recruited five interns (all of whom had previously undertaken 1-year rural clinical school placements), six second year and above doctors, and four advanced skills registrars. RACE has linked with GPEx Rural Generalist registrars and formed a Public Health Unit from those registrars who also have MPH qualifications. RACE and Flinders University are expanding teaching facilities in the region and enabling medical students to complete their MD in the region. DISCUSSION: Health services can facilitate vertical integration of rural medical education, supporting a full pathway to rural practice. Providing length of training contracts is proving attractive for junior doctors who are interested in establishing a rural home base for their training.

Triple quadrupole LC/MS method for the simultaneous quantitative measurement of cefiderocol and meropenem in serum.

Background: therapeutic drug monitoring is a crucial aspect of the management of hospitalized patients. The correct dosage of antibiotics is imperative to ensure their adequate exposure specially in critically ill patients. The aim of this study is to establish and validate a robust and fast liquid chromatography-tandem mass spectrometry (LC/MS) method for the simultaneous quantification of two important antibiotics in critically ill patients, cefiderocol and meropenem in human plasma. Methods: sample clean-up was performed by protein precipitation using acetonitrile. Reverse phase chromatography was performed using triple quadrupole LC/MS. The mobile phase was consisted of 55% methanol in water +0.1% formic acid, with flow rate of 0.4 ml min-1. Antibiotics stability was assessed at different temperatures. Serum protein binding was assessed using ultrafiltration devices. Results: chromatographic separation was achieved within 1.5 minutes for all analytes. Validation has demonstrated the method to be linear over the range 0.0025-50 mg L-1 for cefiderocol and 0.00028-50 mg L-1 for meropenem, with accuracy of 94-101% and highly sensitive, with LLOQ ≈ 0.02 mg L-1 and 0.003 mg L-1 for cefiderocol and meropenem, respectively. Both cefiderocol and meropenem showed a good stability at room temperature over 6 h, and at (4 °C) over 24 h. Cefiderocol and meropenem demonstrated a protein binding of 49-60% and 98%, respectively in human plasma. Conclusion: the developed method is simple, rapid, accurate and clinically applicable for the quantification of cefiderocol and meropenem.

Seropositivity and geographical distribution of Strongyloides stercoralis in Australia: A study of pathology laboratory data from 2012-2016.

BACKGROUND: There are no national prevalence studies of Strongyloides stercoralis infection in Australia, although it is known to be endemic in northern Australia and is reported in high risk groups such as immigrants and returned travellers. We aimed to determine the seropositivity (number positive per 100,000 of population and percent positive of those tested) and geographical distribution of S. stercoralis by using data from pathology laboratories. METHODOLOGY: We contacted all seven Australian laboratories that undertake Strongyloides serological (ELISA antibody) testing to request de-identified data from 2012-2016 inclusive. Six responded. One provided positive data only. The number of people positive, number negative and number tested per 100,000 of population (Australian Bureau of Statistics data) were calculated including for each state/territory, each Australian Bureau of Statistics Statistical Area Level 3 (region), and each suburb/town/community/locality. The data was summarized and expressed as maps of Australia and Greater Capital Cities. PRINCIPAL FINDINGS: We obtained data for 81,777 people who underwent serological testing for Strongyloides infection, 631 of whom were from a laboratory that provided positive data only. Overall, 32 (95% CI: 31, 33) people per 100,000 of population were seropositive, ranging between 23/100,000 (95% CI: 19, 29) (Tasmania) and 489/100,000 population (95%CI: 462, 517) (Northern Territory). Positive cases were detected across all states and territories, with the highest (260-996/100,000 and 17-40% of those tested) in regions across northern Australia, north-east New South Wales and north-west South Australia. Some regions in Greater Capital Cities also had a high seropositivity (112-188/100,000 and 17-20% of those tested). Relatively more males than females tested positive. Relatively more adults than children tested positive. Children were under-represented in the data. CONCLUSIONS/SIGNIFICANCE: The study confirms that substantial numbers of S. stercoralis infections occur in Australia and provides data to inform public health planning.

Process intensification of anaerobic digestion: Influence on mixing and process performance.

The adoption of process intensification to anaerobic digestion can present significant complications for digester mixing and process performance. This work investigated how increasing the solids concentration of the digester sludge influenced the process at various mixing energy inputs. Based on the results, adequate mixing is defined qualitatively as the input of sufficient energy to mobilize the reactor contents without producing significant regions of inhibitory shear force. However, the quantitative definition is dependent on the solids concentration of the sludge. But, the existing design criterion of specific mixing power input based on fluid volume (W/m3) does not represent it well. Therefore, a new design criterion of specific mixing power input based on total solids in the sludge (W/kgTS) is proposed to achieve maximum biogas production using optimum power input. The relationship has its limitations, but it represents a significant step forward in the design and operation of improved digester mixing systems.

Quantitative investigation of hydraulic mixing energy input during batch mode anaerobic digestion and its impact on performance.

The relationship between mixing energy input and biogas production was investigated by anaerobically digesting sewage sludge in lab scale, hydraulically mixed, batch mode digesters at six different specific energy inputs. The goal was to identify how mixing energy influenced digestion performance at quantitative levels to help explain the varying results in other published works. The results showed that digester homogeneity was largely uninfluenced by energy input, whereas cumulative biogas production and solids destruction were. With similar solids distributions between conditions, the observed differences were attributed to shear forces disrupting substrate-microbe flocs rather than the formation of temperature and/or concentration gradients. Disruption of the substrate-microbe flocs produced less favourable conditions for hydrolytic bacteria, resulting in less production of biomass and more biogas. Overall, this hypothesis explains the current body of research including the inhibitory conditions reported at extreme mixing power inputs. However, further work is required to definitively prove it.

Utilization of community health workers in Canada's Children's Oral Health Initiative for indigenous communities.

OBJECTIVE: The Children's Oral Health Initiative (COHI) is a federally funded community-based preventive dental programme implemented in geographically remote Canadian Indigenous communities. The study investigated the effect of the availability of local community health workers (COHI Aides) on access to the programme's preventive dental services for children. METHODS: Twenty-five communities were continuously enrolled in the COHI during the 7-year study period. Communities were categorized as having uninterrupted (all 7 years), intermittent (≥4 years) or sporadic (<4 years) service from a community health worker. Four outcome variables measured longitudinal changes in access to preventive dental services: (i) the number of enrolments; (ii) the number of enrolled children with multiple fluoride varnishes delivered; (iii) the number of enrolled children with sealants placed; and (iv) the number of enrolled children receiving ART. RESULTS: The general longitudinal trend for programme enrolment and each of the preventive dental service delivery outcomes was similar. Children in communities with uninterrupted service tended to have the highest rates of enrolment and service delivery, which remained constant over time. Children in communities with sporadic service tended to have persistently low rates of enrolment and service delivery over the study period. CONCLUSIONS: Community health workers were beneficial in promoting programme enrolment, as well as facilitating and augmenting the delivery of preventive dental services.

The perceptions of first nation participants in a community oral health initiative.

The Children's Oral Health Initiative (COHI) is a federally funded community-based preventive dental program for children and their caregivers living in geographically isolated Canadian Aboriginal communities. The goal of the program is to improve access to preventive dental services for children of 0-7 years of age. It utilises community health workers in collaboration with dental therapists to promote and deliver the program. Almost half of the province of Manitoba's (n=27) First Nations communities have implemented COHI since 2005. The objective of this investigation was to explore the opinions of COHI from the perspective of community members whose children had participated in the program. Purposeful selection identified caregivers of enrolled children for a semi-structured interview. The targeted caregivers had children who met at least one of the following criteria: (1) 0-2 years old; (2) 5-7 years old; (3) had two or more children either currently or formerly enrolled in COHI. Six open-ended questions guided the interview process. Content analysis was used to code transcripts and identify themes. One hundred and forty-one interviews were completed in 13 communities. Participants defined good oral health as the absence of dental cavities, which reflects a Western biomedical model of disease. The local, community-based nature of COHI was viewed as essential to its success in increasing access to preventive dental services and improving children and caregivers' oral health knowledge and behaviours. In conclusion, a local, community-based oral health prevention programme is perceived as having a beneficial effect on children and caregivers' oral health knowledge and behaviours. However, oral health preventive messages need to be further integrated into traditional Aboriginal holistic models of wellness.

Combining Slaughterhouse Surveillance Data with Cattle Tracing Scheme and Environmental Data to Quantify Environmental Risk Factors for Liver Fluke in Cattle.

Liver fluke infection causes serious disease (fasciolosis) in cattle and sheep in many regions of the world, resulting in production losses and additional economic consequences due to condemnation of the liver at slaughter. Liver fluke depends on mud snails as an intermediate host and infect livestock when ingested through grazing. Therefore, environmental factors play important roles in infection risk and climate change is likely to modify this. Here, we demonstrate how slaughterhouse data can be integrated with other data, including animal movement and climate variables to identify environmental risk factors for liver fluke in cattle in Scotland. We fitted a generalized linear mixed model to the data, with exposure-weighted random and fixed effects, an approach which takes into account the amount of time cattle spent at different locations, exposed to different levels of risk. This enabled us to identify an increased risk of liver fluke with increased animal age, rainfall, and temperature and for farms located further to the West, in excess of the risk associated with a warmer, wetter climate. This model explained 45% of the variability in liver fluke between farms, suggesting that the unexplained 55% was due to factors not included in the model, such as differences in on-farm management and presence of wet habitats. This approach demonstrates the value of statistically integrating routinely recorded slaughterhouse data with other pre-existing data, creating a powerful approach to quantify disease risks in production animals. Furthermore, this approach can be used to better quantify the impact of projected climate change on liver fluke risk for future studies.

Perspective: 4ß-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A.

A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug-drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4ß-hydroxycholesterol (4ß-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4ß-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4ß-HC to evaluate changes in CYP3A activity has not been attempted. Herein, we review the biology of 4ß-HC, its response to treatment with CYP3A inducers, inhibitors and mixed inducer/inhibitors in healthy volunteers and patients, the association of 4ß-HC with other probes of CYP3A activity (e.g. midazolam, urinary cortisol ratios), and present predictive pharmacokinetic models. We provide recommendations for studying hepatic CYP3A activity in clinical pharmacology studies utilizing 4ß-HC at different stages of drug development.

The Children's Oral Health Initiative: An intervention to address the challenges of dental caries in early childhood in Canada's First Nation and Inuit communities.

OBJECTIVE: The objective of the Children's Oral Health Initiative (COHI) is to increase access to preventive oral health services provided to First Nations and Inuit (FN/I) children living on federal reserves and in remote communities. PARTICIPANTS: COHI targets preschool children; 5-7-year-olds; pregnant women; and parents/caregivers in FN/I communities. SETTING: The program was piloted in 2004 by Health Canada and is potentially available to all FN/I communities. However, the community must consent to the program's implementation and agree to support a community member to be trained as a COHI aide. INTERVENTION: Dental therapists and hygienists screen eligible children, apply fluoride varnish and sealants to children's teeth, and stabilize active dental caries with glass ionomer. An innovation was the development of a community oral health worker, the COHI Aide. The COHI Aide is a community member who serves as an advocate for preventive oral health in the community and provides instruction to children, parent/caregivers and expectant mothers in preventing dental caries. RESULTS: COHI was piloted in 41 communities in 2004. By 2014, the program had expanded to 320 FN/I communities, which represents 55% of all eligible FN/I communities. In 2012, 23,085 children had received COHI preventive oral health services. CONCLUSION: The results demonstrate COHI's success as a preventive oral health care delivery model in remote communities. Implementation and delivery of preventive oral health services has been enhanced by the sustained presence of a community-based COHI Aide.

Recommendations on the Development of a Bioanalytical Assay for 4ß-Hydroxycholesterol, an Emerging Endogenous Biomarker of CYP3A Activity.

The availability of reliable assays for measuring 4ß-hydroxycholesterol (4ß-HC), a CYP3A metabolite of cholesterol, is an important step in qualifying this endogenous moiety as a biomarker of CYP3A activity. Liquid and gas chromatographic methods with mass spectrometric detection have been developed with varying sensitivities, with or without derivatization. Care must be taken to chromatographically resolve 4ß-HC from the multiple isobaric cholesterol oxidation products present in plasma, including 4α-hydroxycholesterol (4α-HC). Plasma concentrations of 4ß-HC are low in humans (10-60 ng/ml), lower than many other cholesterol metabolites and far less than cholesterol itself. Stability of 4ß-HC has been established for at least 12 months at -20°C in plasma samples obtained with a typical clinical workflow. Oxidation of plasma cholesterol during storage produces both 4ß-HC and 4α-HC, and 4α-HC may be used as assessment of sample quality. As 4ß-HC concentrations over time in untreated individuals have low intra-individual variability, assay precision and reproducibility are the key assay attributes in assessing CYP3A4 induction, and potentially inhibition. Assessment of CYP3A4/5 activity with 4ß-HC relies on the differences between pre- and post-dose concentrations, in which each subject acts as their own control. To reduce analytical variability, samples from a single subject should be analyzed together to facilitate interpretation of study results. As an endogenous biomarker, 4ß-HC offers the opportunity for less invasive assessment of CYP3A induction potential of new drugs during clinical development.

Migration and multiple sclerosis in immigrants from United Kingdom and Ireland to Australia: a reassessment. III: risk of multiple sclerosis in UKI immigrants and Australian-born in Hobart, Tasmania.

Our previous work suggested that migrants from the United Kingdom and Ireland (UKI) to Australia who left their home country at a young age had a longer interval between immigration and onset and likely acquired MS in Australia. In the present study, we reassessed Australian-born cases of MS identified in Hobart, Tasmania, a relatively high-risk zone, in our 1981 survey and compared these with cases of MS in UKI immigrants incident in Australia. The incidence of MS in Australian-born residents rose from 1.63 per 100,000 in 1941-1965 to 3.48 per 100,000 in 1966-1981. The bulk of UKI immigrants who developed MS in Australia migrated after the age of 15 years, and likely acquired their disease in the UKI. The mean interval from immigration to onset differed significantly (p < 0.01) between those migrating before (22 years) versus after (6 years) the age of 15, suggesting acquisition of MS in Australia in the former group. Identified environmental risk factors such as smoking, sunlight and exposure to Epstein-Barr virus do not fully account for the epidemiology of multiple sclerosis. The apparent introduction of MS into Hobart from the mid-1940s on could provide circumstantial support for the theory that MS is a transmissible disease.

The use of laboratory scale reactors to predict sensitivity to changes in operating conditions for full-scale anaerobic digestion treating municipal sewage sludge.

Anaerobic digestion of sewage sludge is highly complex and prone to inhibition, which can cause major issues for digester operators. The result is that there have been numerous investigations into changes in operational conditions, however to date all have focused on the qualitative sensitivities, neglecting the quantitative. This study therefore aimed to determine the quantitative sensitivities by using factorial design of experiments and small semi continuous reactors. Analysis showed total and volatile solids removals are chiefly influenced by retention time, with 79% and 59% of the observed results being attributed to retention time respectively, whereas biogas was mainly influenced by loading rate, 38%, and temperature, 22%. Notably the regression model fitted to the experimental data predicted full-scale performance with a high level of precision, indicating that small reactors are subject to the same sensitivity of full-scale digesters and thus can be used to predict changes loading, retention time, and temperature.

Two studies on reversal of opioid-induced respiratory depression by BK-channel blocker GAL021 in human volunteers.

BACKGROUND: Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed. METHODS: In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI). RESULTS: Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent. CONCLUSION: GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.

Respiratory stimulant drugs in the post-operative setting.

Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. A safe and effective respiratory stimulant could improve patient care by avoiding the use of reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics, facilitate weaning from prolonged ventilation, and ameliorate sleep-disordered breathing peri-operatively. The purpose of this review is to discuss the current pharmaceutical armamentarium of drugs (doxapram and almitrine) that are licensed for use in humans as respiratory stimulants and that could be used to reverse drug-induced respiratory depression in the post-operative period. We also discuss new chemical entities (AMPAkines and GAL-021) that have been recently evaluated in Phase 1 clinical trials and where the initial regulatory registration would be as a respiratory stimulant.

PhRMA survey on the conduct of first-in-human clinical trials under exploratory investigational new drug applications.

The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs. The majority of microdosing studies are performed to characterize human pharmacokinetics or to examine target organ pharmacokinetics using PET imaging techniques. On the other hand, the majority of pharmacological end point studies conducted under exploratory IND are performed to determine whether the compound modulated its pharmacological target or to evaluate the degree of saturation of a target receptor. The present survey suggests that although the merits of exploratory INDs are still being debated, the diversity in the applications cited, the potential for early clinical guidance in decision making and the increasing pressure on containing drug development costs, suggest that the exploratory IND/CTA will be a valuable option with evolving and possibly more specific applications for the future.

Pharmacokinetics of a single dose of the antifungal posaconazole as oral suspension in subjects with hepatic impairment.

OBJECTIVE: To evaluate posaconazole pharmacokinetics in subjects with different degrees of hepatic impairment compared with matched healthy subjects. RESEARCH DESIGN AND METHODS: A total of 37 subjects were enrolled in this open-label, single-dose, parallel-group study; 19 with hepatic impairment and 18 healthy subjects with matching demographics. Each subject received a single 400-mg oral dose of posaconazole after a high-fat meal. Blood samples for analysis were taken up to 648 h ( approximately 4 weeks) postdose. RESULTS: Compared with maximum plasma concentration (C(max)) values in matched subjects with normal hepatic function, values were higher among subjects with moderate hepatic impairment (517 vs. 724 ng/mL) but lower among subjects with severe hepatic impairment (608 vs. 403 ng/mL). No clear trend toward increased or decreased exposure was observed with increasingly severe hepatic impairment, and extensive overlap occurred between normal and hepatically impaired subjects. Therefore, pharmacokinetic variables C(max) and area under the curve from time 0 to the time of final quantifiable sample (AUC(tf)) values were pooled for subjects with hepatic impairment. Pooled C(max) values were similar to the pooled normal groups (607 vs. 605 ng/mL), whereas there was an overall 36% increase in exposure (AUC(tf)) for the pooled hepatic impairment group compared with the pooled normal group. Posaconazole was well-tolerated, with six (33%) healthy subjects and six (32%) hepatically impaired subjects reporting adverse events. CONCLUSIONS: The data from this small single-dose study suggest posaconazole is safe. Furthermore, although limited by the small number of subjects enrolled, the authors feel that dose adjustments are probably not necessary in patients with hepatic impairment; however, physicians should continue to monitor posaconazole use in patients with hepatic impairment.

Individual personality and the spatial distribution of groups of grazing animals: an example with sheep.

Impacts of individual personality on group distribution were investigated using sheep (Ovis aries) as a model. In an indoor exploration test, individuals who visited <4 (out of 6) objects in a novel environment were classified as 'shy' (n=10), and those who visited 5 or 6 objects were classified as 'bold' (n=10). Nine weeks later, using a series of groups (n=40) of either 5 shy or 5 bold sheep, we measured distribution at pasture and responses to disturbance and the approach of a human handler. When grazing undisturbed, the mean nearest neighbour distance and spread (minimum convex hull area) of shy groups were less than those of bold groups, with shy individuals moving towards one another more often. Shy groups explored a smaller area than bold groups. When disturbed, shy sheep were more likely to stop grazing and move closer together. Shy sheep kept further away from the handler and moved faster when driven. The results demonstrate a link between personality and group distribution, suggesting that our 'shy' and 'bold' individuals may occupy different positions on the shy-bold continuum documented for other species. We discuss implications for diet composition and impacts on vegetation grazed by animals with different personalities.

Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers.

BACKGROUND: Like itraconazole and ketoconazole, posaconazole, a broad-spectrum oral triazole antifungal, inhibits the activity of the cytochrome P450 (CYP) isozyme 3A4. Midazolam, a short-acting benzodiazepine, is metabolized by CYP3A4. Potential drug interactions can be expected in patients who are concurrently receiving inhibitors and substrates of CYP3A4 (eg, ketoconazole, posaconazole) and benzodiazepines (eg, midazolam). Because of the potential for drug interactions, it is important to determine the effects of posaconazole on the pharmacokinetic properties of midazolam. OBJECTIVE: The aim of this study was to compare the effects of oral administration of posaconazole versus ketoconazole on the pharmacokinetic properties of orally and intravenously administered midazolam. METHODS: This Phase I, randomized, open-label, crossover study was conducted at Swiss Pharma Contract Ltd., Allschwil, Switzerland. Healthy volunteers were randomly assigned to 1 of 2 treatment arms. Arm 1 received posaconazole 200 mg BID for 7 days, posaconazole 400 mg BID for 7 days, no drugs during a 28-day washout, and ketoconazole 400 mg once daily for 7 days. Arm 2 received posaconazole and ketoconazole in the reverse order, with a 28-day washout between treatments. An oral/IV midazolam sequence (oral midazolam 2 mg and IV midazolam 0.4 mg) was administered on days -2/-1, 6/7, 13/14 (arm 1), 36/17 (arm 2), 43/44, and 50/51 in both treatment arms. Blood samples were collected up to 24 hours after midazolam administration. Pharmacokinetic parameters, including C(max), C(min) (before azole administration), terminal-phase t(1/2) (t(1/2z)), and AUC to final measurable sampling time (AUC(tf)), were calculated using noncompartmental methods, and drug interactions were evaluated using analysis of variance. Adverse events were collected using physical examination, including vital sign measurements; clinical laboratory analysis; electrocardiography; and direct questioning at predefined time points throughout the study to assess tolerability. RESULTS: A total of 12 subjects were enrolled (11 men, 1 woman; all white; mean age, 42.8 years [range, 28-53 years]; mean weight, 80.6 kg; and mean body mass index, 25.6 kg/m(2)). All of the subjects completed the study. Based on point estimates of logarithm-transformed data, posaconazole 200 and 400 mg BID were associated with significant increases in midazolam C(max) (up to 1.3- and 2.4-fold) and AUC(tf) values (up to 4.6- and 6.2-fold), respectively. Ketoconazole 400 mg once daily was associated with significantly increased midazolam C(max) and AUC(tf) (up to 2.8- and 8.2-fold, respectively). When midazolam was concurrently administered with either azole, t(1/2z) was prolonged. Seven of 12 (58%) subjects reported > or =1 adverse event during the study (5 with posaconazole alone and 4 with posaconazole + midazolam). The most common adverse events were diarrhea (3 subjects [25%] with posaconazole alone, 2 [17%] with ketoconazole alone, and 1 [8%] with posaconazole + midazolam) and flatulence (1 [8%] with posaconazole alone and 1 [8%] with midazolam alone). CONCLUSIONS: The results from this study in a small, all-white population of healthy volunteers suggest that posaconazole was a potent inhibitor of CYP3A4, but to a lesser extent than was ketoconazole. Monitoring patients for adverse events, the need for dose adjustments, or both during coadministration with posaconazole may be warranted in patients being treated with benzodiazepines that are predominantly metabolized through CYP3A4 (eg, midazolam).