Assessment of Micafungin Dosage Regimens in Patients with Cancer Using Pharmacokinetic/Pharmacodynamic Modeling and Monte Carlo Simulation

Micafungin is widely used for invasive candidiasis, especially in critically ill patients and those with cancer, and for empirical antifungal therapy in patients with neutropenic fever. This is the first study to investigate the pharmacokinetics and disposition parameters of micafungin in patients with cancer. In this observational pharmacokinetic study, blood samples were collected and analyzed using high-performance liquid chromatography. Pharmacokinetic parameters were estimated using Monolix 4.4 software. The plasma micafungin concentrations were measured in a total of 133 samples from 19 patients. In the final two-compartment model with linear elimination, the estimated micafungin clearance (CL) was significantly higher in patients with cancer than in those without cancer (1.2 vs. 0.6 L/h, p = 0.012), whereas other parameters did not significantly differ between the two groups. Aspartate and alanine transaminases and body weight significantly influenced micafungin CL in patients, with and without cancer. Overall, the probability of target attainment increased with increasing doses and decreased with higher MICs in both groups. In simulations, the patients without cancer achieved higher pharmacokinetic/pharmacodynamic targets with a 90% probability for all simulated doses, compared to the patients with cancer. Micafungin demonstrated dose-proportional linear pharmacokinetics in both the patients with and those without cancer. The estimated micafungin CL was significantly higher in patients with cancer, suggesting a need for increased dosage, especially for Candida spp. with high MICs, in these patients. Further studies should assess the efficacy and optimum dosage of micafungin for the treatment and prevention of febrile neutropenia (FN) in patients with cancer.

Population Pharmacokinetics of Rezafungin in Patients with Fungal Infections

Rezafungin is a novel antifungal agent of the echinocandin class with potent activity against species of Candida and Aspergillus , including subsets of resistant strains, and Pneumocystis jirovecii . The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration in healthy volunteers and in patients with candidemia and/or invasive candidiasis. The population PK model was based on a previous model from Phase 1 data; formal covariate analyses were conducted to identify any relationships between subject characteristics and rezafungin PK variability. A four-compartment model with linear elimination and zero-order drug input provided a robust fit to the pooled data. Several statistically significant relationships between subject descriptors [sex, infection status, serum albumin, and body surface area (BSA)] and rezafungin PK parameters were identified but none were deemed clinically relevant. Previous dose justification analyses conducted using data from Phase 1 subjects alone are expected to remain appropriate. The final model provided a precise and unbiased fit to the observed concentrations and can be used to reliably predict rezafungin PK in infected patients.

Computing Optimal Hypertree Decompositions with SAT

Hypertree width is a prominent hypergraph invariant with many algorithmic applications in constraint satisfaction and databases. We propose a novel characterization for hypertree width in terms of linear elimination orderings. We utilize this characterization to generate a new SAT encoding that we evaluate on an extensive set of benchmark instances. We compare it to state-of-the-art exact methods for computing optimal hypertree width. Our results show that the encoding based on the new characterization is not only significantly more compact than known encodings but also outperforms the other methods.

Pharmacokinetics of Polymyxin B in Hospitalized Adults with Cystic Fibrosis

Background: The optimal polymyxin B dosage needed to achieve an efficacy target of 50-100 mg·h/L when treating multi-drug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. Methods: This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50-100 mg every 12 hours. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents, B1 and B2, were quantified using Liquid Chromatography Mass Spectrometry (LC-MS). Population PK (NONMEM® software) analysis was performed using pooled polymyxin B1+B2 concentrations. Results: Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21-57 years) and 58.0kg (range 38.3-70.4kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution, 2.09 L/hr and 12.7 L, respectively, corresponding to a 4.1 hour mean half-life (t 1/2 ). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 hours was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients; acute kidney injury events in two patients. These events resolved within 2-4 days after discontinuing polymyxin B. Conclusions: Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.

Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

Aims Mycophenolic acid (MPA) is typically used for anti-neutrophilic cytoplasmic antibody associated nephritis (AAN) but with large individual variability of pharmacokinetics. This study aims to investigate clinical factors impacting MPA disposal so as to simulate dosage regimen in pediatric AAN. Methods We conducted a retrospective study in 25 children with AAN treated with MPA. A population pharmacokinetic model was developed to explore the effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimens. Results A total of 391 MPA concentrations from 25 patients were analyzed. MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL, Vc, Vp, and Q were 0.45 h-1, 9.86 L/h, 19.69 L, 408.32 L and 23.01 L/h, respectively. Dosage form significantly affected drug absorption. CL significantly decreased with increasing cystatin C, while with decreasing myeloperoxidase. Cystatin C was superior to serum creatinine in predicting CL of MPA. A dose of 650 mg/m2 was required to achieve the target exposure in children with normal renal function and no inflammation. Dose of MPA in patients with renal failure was almost 1/3 that of normal kidney function. The combined effects of myeloperoxidase and renal function resulted in a 6-fold range in MPA dose. Conclusions Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN children.

Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug

Proton pump inhibitors (PPIs) are the mainstay for treatment of acid-related diseases. This study developed a mechanism-based pharmacokinetic (PK) and pharmacodynamics (PD) model with ilaprazole as case drug, so as to support and accelerate the development of novel PPIs. The model was established and verified using the PK and PD data from 26 subjects receiving 5 to 30 mg of ilaprazole and 22 subjects receiving the loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days. The nonlinear mixed-effects modeling approach was performed for the PK/PD model. A two-compartment model with linear elimination and covariates (body weight and gender) described the observed data well. The relationship between plasma concentrations of ilaprazole and gastric acid pH was well quantified with individual variability, in which the synthesis and degradation of H+/K+-ATPase, the food effect, the circular rhythms of gastric acid secretion, and the irreversible inhibition of H+/K+-ATPase by ilaprazole were integrated. This PK/PD model well predicted the PK and PD profile of ilaprazole in healthy subjects and patients with duodenal ulcers receiving wide range dose regimens. The mechanism-based PK/PD model provided a potential strategy to accelerate the development of novel PPIs by waiving the unnecessary clinical trials.

Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children

Ivermectin is a broad-spectrum antiparasitic agent used for the treatment and control of neglected tropical diseases. In Australia, ivermectin is primarily used for scabies and is licensed in children aged ≥5 years weighing >15 kg. However, young children, aged <5 years, are particularly vulnerable to scabies and its secondary complications. Therefore, this study aimed to determine an appropriate ivermectin dose for children aged 2 to 4 years and weighing ≤15 kg. We conducted a prospective, pharmacokinetic study of ivermectin in Indigenous Australian children aged between 5 and 15 years and weighing >15 kg. Doses of 200 μg/kg rounded to the nearest whole or half 3 mg tablet were given to children with scabies and ivermectin concentrations determined at two time points after dosing. A population pharmacokinetic model was developed using non-linear mixed effects modelling. A separate covariate database of children aged 2 to 4 years and weighing <15 kg was used to generate 1000 virtual patients and simulate the dose required to achieve equivalent drug exposure in young children as those aged ≥5 years. Overall, 26 children who had 48 ivermectin concentrations determined were included, 11 (42%) were male, the median age was 10.9 years and median body weight 37.6 kg. The final model was a two-compartment model with first-order absorption and linear elimination. For simulated children aged 2 to 4 years, a dose of 3 mg in children weighing 10–15 kg produced similar drug exposures to those >5 years. The median simulated area under the concentration-time curve was 976 μg∙h/L. Using modelling, we have identified a dosing strategy for ivermectin in children aged 2 to 4 years and weighing less than 15 kg that can be prospectively evaluated for safety and efficacy.

Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy

Background. Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. Methods. The pharmacokinetics and pharmacodynamics (PK/PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of Aspergillus fumigatus IPA at doses between 2 and 20 mg/kg and day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics Package in R. Results. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by a dynamic Hill-functions reflecting growth and kill of the fungus. Through calculations of the AUC0-24h at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC0-24h of 30 mg*h/L. All prophylactic doses were able to control the fungal burden. Conclusions. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC0-24h greater than 30 mg*h/L was associated with adequate resolution of the GMI, which is well in support of previously suggested exposure-response relationships in humans.

Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa

Background Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.

Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment

ABSTRACT Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/PD targets were evaluated: 100% free time (fT) > 1× MIC and 100% fT > 4× MIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into nonrenal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT > 1× MIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT > 4× MIC. Probability of target attainment for a simulated cohort of patients showed that increasing the daily dose by 4-g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT > 4× MIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a continuous infusion (CI) regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.