Forecast of omicron wave time evolution

Adopting an early doubling time of three days for the rate of new infections with the omicron mutant the temporal evolution of the omicron wave in different countries is predicted. The predictions are based on the susceptible-infectious-recovered/removed (SIR) epidemic compartment model with a constant stationary ratio k=mu(t)/a(t) between the infection (a(t)) and recovery (mu(t)) rate. The fixed early doubling time then uniquely relates the initial infection rate a0 to the ratio k, which therefore determines the full temporal evolution of the omicron waves. For each country three scenarios (optimistic, pessimistic, intermediate) are considered and the resulting pandemic parameters are calculated. These include the total number of infected persons, the maximum rate of new infections, the peak time and the maximum 7-day incidence per 100000 persons. Among the considered European countries Denmark has the smallest omicron peak time and the recently observed saturation of the 7-day incidence value at 2478 is in excellent agreement with the prediction in the optimistic scenario. For Germany we predict peak times of the omicron wave ranging from 32 to 38 and 45 days after the start of the omicron wave in the optimistic, intermediate and pessimistic scenario, respectively, with corresponding maximum SDI values of 7090, 13263 and 28911, respectively. Adopting Jan 1st, 2022 as the starting date our predictions implies that the maximum of the omicron wave is reached between Feb 1 and Feb 15, 2022. Rather similar values are predicted for Switzerland. Due to an order of magnitude smaller omicron hospitalization rate, due to the high percentage of vaccinated and boostered population, the German health system can cope with maximum omicron SDI value of 2800 which is about a factor 2.5 smaller than the maximum omicron SDI value 7090 in the optimistic case. By either reducing the duration of intensive care during this period of maximum, and/or by making use of the nonuniform spread of the omicron wave across Germany, it seems that the German health system can barely cope with the omicron wave avoiding triage decisions. The reduced omicron hospitalization rate also causes significantly smaller mortality rates compared to the earlier mutants in Germany. In the optimistic scenario one obtains for the total number of fatalities 7445 and for the maximum death rate 418 per day which are about one order of magnitude smaller than the beta fatality rate and total number.

Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

Target attainment of extended-interval dosing of tobramycin in patients less than five years of age with cystic fibrosis: A pharmacokinetic analysis.

Background: Extended interval dosing (EID) of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age.Methods:We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM® using data from the first 48 hours of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once daily dosing. Results:Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A 2-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once daily regimens achieved all pre-specified targets simultaneously in >75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax >25 mg/L and AUC24 of 80-120 mg*h/L.Conclusions:Based on our population PK analysis and simulations, once daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.

Effects of housing environment on oral absorption of acetaminophen in healthy Beagles

OBJECTIVE To evaluate the effects of housing environment on oral absorption of acetaminophen in dogs. ANIMALS 6 healthy Beagles. PROCEDURES Acetaminophen (325 mg, PO; mean dose, 31.1 mg/kg) was administered in a crossover study design with dogs housed in their normal environment or in a cage in an unfamiliar environment. There was a 7-day washout period between phases. Blood samples were collected for 24 hours following acetaminophen administration, and plasma acetaminophen concentrations were determined with high-pressure liquid chromatography. RESULTS A 2-compartment model with lag time was the best fit for both phases of the study. None of the primary or secondary pharmacokinetic parameters were significantly different between the 2 housing environments. CLINICAL RELEVANCE Findings suggested that in dogs, housing environment (normal environment vs a cage in an unfamiliar environment) did not significantly affect oral absorption and, by extension, gastric emptying of acetaminophen.

Effects of Drugs Reabsorption Time Delays for a Pharmacokinetics Model in Humans

A three-compartmental delay model is formulated to describe the pharmacokinetics of drugs subjected to both intravenous and oral doses with reabsorptions by the central compartment. Model dynamics are analyzed rigorously, and two equilibrium points are obtained to be locally asymptotically stable under certain conditions. Time delays used as lags in reabsorption of drugs by central compartment from other two compartments caused rebounds or peaks and fluctuations in the time profiles for amounts of drug in all the compartments. Sensitivity analysis revealed that elimination rates decrease the amounts in all compartments. Furthermore, reabsorption rates cause superimposition at the initial phases of the drug amount profiles; subsequently, the quantities decrease in compartment one and increase in compartments two and three, respectively.

Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device

Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.