The effect of isoniazid intake on ethionamide pharmacokinetics and target attainment in multidrug-resistant tuberculosis patients.

Ethionamide is recommended as part of regimens to treat multidrug-resistant and rifampicin-resistant tuberculosis. The study was conducted to (i) describe the distribution of ethionamide minimum inhibitory concentrations (MICs), (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target AUC 0-24 /MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15–20 mg/kg of ethionamide daily (in 500 or 750 mg doses), as part of a multidrug regimen. Pretreatment MICs of ethionamide for M. tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured pre-dose and at 2, 4, 6, 8 and 10 hours post-dose) were available for 84 patients. A one-compartment disposition model including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid co-administration reduced ethionamide clearance by 31% resulting in a 44% increase in AUC 0-24 . The median (range) MIC (n=111) was 2.5 mg/L (<0.3 to >40 mg/L). Simulations showed increased daily doses of ethionamide (1 250 mg, 1 500 mg, and 1 750 mg for patients weighing ≤45 kg, 46-70 kg, and >70 kg, respectively) resulted in the probability of attaining a f AUC 0-24 /MIC ratio ≥ 42 in more than 90% of patients, only at the lowest MIC of 0.3 mg/L. The WHO recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.

Elevated insulin levels following 7 days of increased sedentary time are due to lower hepatic extraction and not higher insulin secretion

Higher insulin following sedentary behavior may be due to increased insulin secretion (IS), decreased hepatic insulin extraction (HIE), or a combination of both. Ten healthy adults completed glucose tolerance tests following 7 days of normal activity and 7 days of increased sitting. There were no differences in IS; however, HIE at 120 min after ingestion (85.4% ± 7.2% vs. 74.6% ± 6.6%, p < 0.05) and the area under the curve (73.6% ± 9.4% vs. 67.5% ± 11.3%, p < 0.05) were reduced following 7 days of increased sedentary time.

Safety profile of pharmacotherapy in paitionts with non-alcogolic fatty liver disease

NAFLD is a leader among chronic liver diseases worldwide. Polymorbidity of such patients requires the appointment of different groups of drugs. The quality of pharmacological correction, which is determined in achieving the desired therapeutic effect and the absence of adverse reactions of the therapy, depends on the functional state of the liver. In diseases of the liver clearance of drugs is reduced, and the period of their half-life increases. Thus, drugs with high hepatic extraction may increase the risk of overdose. In this connection, prior to therapy, laboratory and instrumental control of liver function is necessary to reduce the risk of its drug damage, side effects of pharmacotherapy and prevention of complications.

HYALURONIDASE: AN EXPERIMENTAL CONFIRMATION OF THE PROPERTIES OF THE ENDOLYMPHATIC CONDUCTOR

One of the major achievements of contemporaneous pharmacology is the clinical implementation of the agents (the so called “endolymphatic conductors”) that allow for targeted delivering of antibiotic into the lymphatic system. Their use provides the basis for the lymphotropic treatment method that has been implemented into various areas of medical practice. Hyaluronidase is the most known agent used for this purpose. It has been shown that its preliminary administration before the injection of an antibiotic can improve clinical efficacy of the treatment; however, there is a need in the experimental validation of this approach to antibacterial therapy. The study was aimed at evaluation of hyaluronidase effects on the rate of lymphatic drainage of tissues and cefotaxime pharmacokinetics. We measured the time of elimination of lymphotropic Evans blue dye from the mouse mesentery when administered against the background of hyaluronidase, changes in cefotaxime levels over 24 hours in rabbit plasma and in mice plasma, gut tissues and liver at 1,5 and 24 hours after combined administration of hyaluronidase and the antibiotic. In addition, we calculated the liver to plasma ratio for the antibiotic concentrations. The data obtained shows that hyaluronidase can stimulate tissue lymphatic drainage. Its preliminary administration results in higher cefotaxime levels in rabbit and mice plasma at all time points of the study, compared to cefotaxime monotherapy, with prolongation of its systemic circulation of up to 24 hours. The use of cefotaxime after hyaluronidase leads to an increase of its levels in the mice gut tissues both at 1,5 and 24 hours, but has no effect on the antibiotic accumulation in the liver of the animals. However, the calculated liver to plasma blood ratio of cefotaxime after the administration of hyaluronidase is significantly lower than in the animals with the antibiotic monotherapy. This may indirectly indicate to a decrease in the hepatic extraction of the antibiotic when administered with hyaluronidase. The study results confirm that hyaluronidase has the properties of a lymphatic stimulator and an endolymphatic conductor for the water-soluble antibiotic cefotaxime.

Lymphatic Drug Absorption via the Enterocytes: Pharmacokinetic Simulation, Modeling, and Considerations for Optimal Drug Development

Most orally administered drugs gain access to the systemic circulation by direct passage from the enterocyte layer of the intestinal tract to the mesenteric blood capillaries. Intestinal lymphatic absorption is another pathway that certain drugs may follow to gain access to the systemic circulation after oral administration. Once absorbed, drug diffuses into the intestinal enterocyte and while in transit may associate with fats as they are processed into chylomicrons within the cells. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, thus avoiding the hepatic first-pass liver metabolism, and ultimately entering to the systemic circulation for disposition and action. Due to the possibility of parallel and potentially alternative absorptive pathways, mesenteric blood capillary and lymphatic drug exposure are both potential pathways of systemic availability for any individual drug. In this report, an in silico modeling approach was adopted to delineate the salient pharmacokinetic features of lymphatic absorption, and provide further guidance for the rationale design of drugs and drug delivery systems for lymphatic drug transport. The importance of hepatic extraction ratio, absorption lag time, lipoprotein binding, and the influence of competing portal and lymphatic pathways for systemic drug availability were explored using simulations. The degree of hepatic extraction was found to be an essential consideration when examining the influence of lymphatic uptake to overall oral drug bioavailability. Lymphatic absorption could potentially contribute to multiple peaking phenomena and flip flop pharmacokinetics of orally administered drugs.

The utility of genomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study.

2564 Background: BSA-based dosing of Irinotecan (IR), does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variability. Given IR’s unique metabolism, functional hepatic nuclear imaging (HNI) with probes for hepatic transporters correlated with its PK. This study further evaluated the utility of HNI combined with extensive excretory/metabolic/PD pharmacogenomics (PG) to predict IR PK and PD in patients (pts) treated with FOLFIRI to enable dose individualization. Methods: Eligible pts had advanced colorectal cancer, suitable for 1st/2nd-line FOLFIRI± Bevacizumab. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional SNPs were genotyped. For HNI, pts were given IV 250MBq 99mTc-IDA and imaging data analyzed for hepatic extraction/excretion parameters (clearance [CL], 1hour retention [1hRET], deconvulutional CL [DeCL], hepatic extraction fraction [HEF]). Pts treated with chemotherapy, q2-weekly, and restaged after 4 cycles. Blood taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1, PK parameters derived by non-compartmental analysis. Statistical correlations were evaluated between (i) IDA HNI and (2) PGs, with IR PK, toxicity, objective response (ORR) and progression-free survival (PFS). Results: 32 pts analysed, 31 pts completed 4 cycles. (1) PK correlates: (a) HNI CL and 1hRET with SN38 Metabolic CL, (P = 0.04) and (b) HNI DeCL with IR AUC(0-∞) (P = 0.04). (2) Grade 3+ diarrhea (N = 4, 13%) predicted by SN38 AUC(0-∞) and Metabolic CL (P = 0.04), and gene variants for SCL22A2 and -28A3, ABCC2, UGT2B17, CYP2C18 and DPYD (P < 0.05). (3) Grade 3+ neutropenia (N = 9, 28%) predicted by SN38 PK exposure (P < 0.02), HNI CL and 1hRET (P < 0.0001) and variants for SLC7A7-, SLC22A2-, CHST1-, UGT1A1-, -2B7, ABCB1. (4) ORR (N = 6, 20%) predicted by Methylene tetrahydrofolate reductase (MTHFR) 677C > T (P = 0.002), SN38 exposure (P < 0.003), and variants in metabolic/transporter genes (P < 0.05). (5) PFS by SN38 PK exposure, MTHFR 677C > T, HNI CL, HNI HEF and variants in PK genes (P < 0.05). Conclusions: Hepatic functional imaging with extensive pharmacogenomics correlate with Irinotecan PK and PD enabling the development of nomograms to individualize dosing. Clinical trial information: ACTRN12610000898055.