Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study.

Voriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care. The best way to adjust dosages to achieve desired drug exposure endpoints is unclear due to nonlinear and variable pharmacokinetics. Previously described software was used to prospectively adjust voriconazole dosages. The CYP2C19, CYP3A4, and CYP3A5 genotypes were determined. The primary endpoint was the proportion of patients with a Cmin at 120 h in the range 1 to 3 mg/liter using software to adjust voriconazole dosages. A total of 19 patients were enrolled, and 14 were evaluable. Of these, 12/14 (85.7%; 95% confidence interval = 57.2 to 98.2%) had a Cmin at 120 h posttreatment initiation of 1 to 3 mg/liter, which was higher than the a priori expected proportion of 33%. There was no association of CYP genotype-derived metabolizer phenotype with voriconazole AUC. Software can be used to adjust the dosages of voriconazole to achieve drug exposures that are safe and effective. (The clinical trial discussed in this paper has been registered in the European Clinical Trials Database under EudraCT no. 2013-0025878-34 and in the ISRCTN registry under no. ISRCTN83902726.).

Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease.

Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans, with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal ß-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log10CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.

Ethambutol Partitioning in Tuberculous Pulmonary Lesions Explains Its Clinical Efficacy.

Clinical trials and practice have shown that ethambutol is an important component of the first-line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against nongrowing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here, we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First, we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions. We then employed mass spectrometry imaging and laser capture microdissection coupled to liquid chromatography and tandem mass spectrometry (LCM and LC/MS-MS, respectively) to show that ethambutol, indeed, accumulates in diseased tissues and penetrates the major human-like lesion types represented in the rabbit model of TB disease with a lesion-to-plasma exposure ratio ranging from 9 to 12. In addition, ethambutol exhibits slow but sustained passive diffusion into caseum to reach concentrations markedly higher than those measured in plasma at steady state. The results explain why ethambutol has retained its place in the first-line regimen, validate our in vitro lesion penetration assays, and demonstrate the critical importance of effective lesion penetration for anti-TB drugs. Our findings suggest that in vitro and in vivo lesion penetration evaluation should be included in TB drug discovery programs. Finally, this is the first time that LCM with LC-MS/MS has been used to quantify a small molecule at high spatial resolution in infected tissues, a method that can easily be extended to other infectious diseases.

Experimental Models of Short Courses of Liposomal Amphotericin B for Induction Therapy for Cryptococcal Meningitis.

Cryptococcal meningoencephalitis is a rapidly lethal infection in immunocompromised patients. Induction regimens are usually administered for 2 weeks. The shortest effective period of induction therapy with liposomal amphotericin B (LAMB) is unknown. The pharmacodynamics of LAMB were studied in murine and rabbit models of cryptococcal meningoencephalitis. The concentrations of LAMB in the plasma and brains of mice were measured using high-performance liquid chromatography (HPLC). Histopathological changes were determined. The penetration of LAMB into the brain was determined by immunohistochemistry using an antibody directed to amphotericin B. A dose-dependent decline in fungal burden was observed in the brains of mice, with near-maximal efficacy achieved with LAMB at 10 to 20 mg/kg/day. The terminal elimination half-life in the brain was 133 h. The pharmacodynamics of a single dose of 20 mg/kg was the same as that of 20 mg/kg/day administered for 2 weeks. Changes in quantitative counts were reflected by histopathological changes in the brain. Three doses of LAMB at 5 mg/kg/day in rabbits were required to achieve fungicidal activity in cerebrospinal fluid (cumulative area under the concentration-time curve, 2,500 mg · h/liter). Amphotericin B was visible in the intra- and perivascular spaces, the leptomeninges, and the choroid plexus. The prolonged mean residence time of amphotericin B in the brain suggests that abbreviated induction regimens of LAMB are possible for cryptococcal meningoencephalitis.

Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children.

Liposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited pharmacokinetic (PK) data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults. Our objective was to describe the pharmacokinetics of LAmB in children aged 1 to 17 years with suspected or documented IFD. Thirty-five children were treated with LAmB at doses of 2.5 to 10 mg kg-1 daily. Samples were taken at baseline and at 0.5- to 2.0-h intervals for 24 h after receipt of the first dose (n = 35 patients) and on the final day of therapy (n = 25 patients). LAmB was measured using high-performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored. An evolution in PK was observed during the course of therapy, resulting in a proportion of patients (n = 13) having significantly higher maximum serum concentrations (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) later in the course of therapy, without evidence of drug accumulation (trough plasma concentration accumulation ratio of <1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24 and probability of nephrotoxicity (odds ratio, 2.37; 95% confidence interval, 1.84 to 3.22; P = 0.004). LAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation, or observed clinical factors.

Vancomycin toxicity in neonates: a review of the evidence.

PURPOSE OF REVIEW: Vancomycin is a first-line agent in the treatment of serious Gram-positive infections in the neonatal population. The published evidence on vancomycin toxicity in neonates is limited. This review summarizes preclinical studies and clinical trials describing vancomycin toxicity. We discuss proposed pathophysiology and summarize evidence supporting dose-response relationships, genetic and environmental determinants, and consider future research required to further define vancomycin toxicity. RECENT FINDINGS: Current dosing regimens for vancomycin result in subtherapeutic levels in a large proportion of patients. Higher daily doses have been proposed, which have led to concerns regarding increased toxicity. Nephrotoxicity occurs in 1-9% of neonates receiving currently recommended doses. The incidence is highest in those receiving concomitant nephrotoxic drugs. Vancomycin-associated ototoxicity is rare in patients of all ages. Exposure-toxicity relationships in relation to nephrotoxicity and ototoxicity have not been clearly defined in neonates receiving vancomycin. SUMMARY: Current evidence supports the favourable safety profile of vancomycin in neonates. Further studies that address safety concerns relating to high-dose intermittent dosing regimens are needed. Such studies must include robust and standardized definitions of renal and hearing impairment, and include follow-up of sufficient length to establish the long-term implications of experimental findings.

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future.

Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections.

INTRODUCTION: Fungal infections are a major source of global morbidity and mortality. Itraconazole is a triazole antifungal agent that is widely used for the prevention and treatment of fungal infection. While newer antifungal agents are now available, itraconazole is an orally bioavailable agent with broad-spectrum antifungal activity. Itraconazole remains a useful drug for the management of allergic and invasive mycoses worldwide. AREAS COVERED: This article provides a summary of the pharmacokinetics, pharmacodynamics and clinical uses of itraconazole. Additionally, the authors summarise the safety and recently described toxicodynamics and discuss the value of therapeutic drug monitoring (TDM) with itraconazole. The following search criteria were constructed in order to identify relevant literature using PubMed and Ovid-MEDLINE: itraconazole, triazole, pharmacokinetics, pharmacodynamics, toxicodynamics and TDM. Relevant abstracts and articles identified from reviewing secondary citations were additionally retrieved and included if relevant. EXPERT OPINION: Itraconazole remains an important agent in the prevention and treatment of fungal infection. Itraconazole has a broad-spectrum of activity and is available in both an intravenous and oral form making long-term use in chronic mycoses practical. Itraconazole is widely used for the treatment of endemic fungal infections. Pharmacokinetic variability and clinically important drug interactions make TDM of itraconazole an important consideration.

Antifungal agents and therapy for infants and children with invasive fungal infections: a pharmacological perspective.

Invasive fungal infections, although relatively rare, are life-threatening diseases in premature infants and immunocompromised children. While many advances have been made in antifungal therapeutics in the last two decades, knowledge of the pharmacokinetics and pharmacodynamics of antifungal agents for infants and children remains incomplete. This review summarizes the pharmacology and clinical utility of currently available antifungal agents and discusses the opportunities and challenges for future research.

Delineating the 17q24.2-q24.3 microdeletion syndrome phenotype.

We present an 11-year-old girl with a 2.3 Mb de novo interstitial deletion in chromosome 17q24.2-q24.3 identified by array CGH. The phenotype in this case includes skeletal malformations (lower limb bowing, progressive scoliosis and dental abnormalities), feeding problems, mild learning difficulties, and a characteristic facial appearance. Much of the phenotype is attributable to the deletion of KCNJ2, which causes Andersen Tawil Syndrome (ATS), but the facial appearance is not typical. We hypothesise that the presence of mild channelopathy-related features seen in ATS may be explained by haplo-insufficiency, leading to a reduced number of functionally normal Kir2.1 channels. Comparison is made to previous reports describing overlapping 17q deletions, and potential candidate genes which account for the specific phenotypic similarities with this case are highlighted.

Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy.

BACKGROUND: Posaconazole is a triazole with anti-Aspergillus activity. However, little is known about the utility of posaconazole as primary therapy for invasive pulmonary aspergillosis. METHODS: An in vitro model of the human alveolus was used to study the impact of minimum inhibitory concentrations (MIC) on exposure-response relationships. The pharmacokinetic-pharmacodynamic relationships of posaconazole were examined in an inhalational murine model of invasive pulmonary aspergillosis. A mathematical model was fitted to the entire data set. This model was then used to describe the relationship between drug exposure, quantified in terms of the area under the concentration time curve to MIC (AUC:MIC) and the observed antifungal effect. RESULTS: The posaconazole MIC was an important determinant of exposure-response relationships and accounted for a portion of the observed variance. Murine pharmacokinetics were linear for dosages 1-20 mg/kg/day. There was a dose-dependent decline in serum galactomannan concentrations, with near-maximal suppression following 20 mg/kg/day. The murine pharmacokinetic-pharmacodynamic data were well described by the mathematical model. An AUC:MIC ratio of 167 was associated with half-maximal antifungal effect. CONCLUSIONS: These results provide the experimental foundation for the selection of candidate posaconazole regimens for the primary treatment of invasive pulmonary aspergillosis in profoundly neutropenic hosts.

Pharmacokinetics and pharmacodynamics of amphotericin B deoxycholate, liposomal amphotericin B, and amphotericin B lipid complex in an in vitro model of invasive pulmonary aspergillosis.

The pharmacodynamic and pharmacokinetic (PK-PD) properties of amphotericin B (AmB) formulations against invasive pulmonary aspergillosis (IPA) are not well understood. We used an in vitro model of IPA to further elucidate the PK-PD of amphotericin B deoxycholate (DAmB), liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC). The pharmacokinetics of these formulations for endovascular fluid, endothelial cells, and alveolar cells were estimated. Pharmacodynamic relationships were defined by measuring concentrations of galactomannan in endovascular and alveolar compartments. Confocal microscopy was used to visualize fungal biomass. A mathematical model was used to calculate the area under the concentration-time curve (AUC) in each compartment and estimate the extent of drug penetration. The interaction of LAmB with host cells and hyphae was visualized using sulforhodamine B-labeled liposomes. The MICs for the pure compound and the three formulations were comparable (0.125 to 0.25 mg/liter). For all formulations, concentrations of AmB progressively declined in the endovascular fluid as the drug distributed into the cellular bilayer. Depending on the formulation, the AUCs for AmB were 10 to 300 times higher within the cells than within endovascular fluid. The concentrations producing a 50% maximal effect (EC50) in the endovascular compartment were 0.12, 1.03, and 4.41 mg/liter for DAmB, LAmB, and ABLC, respectively, whereas, the EC50 in the alveolar compartment were 0.17, 7.76, and 39.34 mg/liter, respectively. Confocal microscopy suggested that liposomes interacted directly with hyphae and host cells. The PK-PD relationships of the three most widely used formulations of AmB differ markedly within an in vitro lung model of IPA.

Tremor: a newly described adverse event with long-term itraconazole therapy.

Itraconazole is a widely prescribed triazole antifungal drug, often given for long periods. The authors report five cases of tremor related to itraconazole therapy, which occurred within 1-12 months of initiating treatment and resolved gradually following itraconazole withdrawal.

Toxicodynamics of itraconazole: implications for therapeutic drug monitoring.

We explored concentration-toxicity relationships for itraconazole among 216 patients. Logistic regression revealed a progressive increase in the probability of toxicity with increasing concentrations of itraconazole. Classification and regression tree analysis suggested that 17.1 mg/L of itraconazole (measured using a bioassay) was the concentration level at which the population of patients was separated into 2 groups, each with a high and a low probability of toxicity.