Pharmacokinetic Data In Patients Research Articles

Mirikizumab Pharmacokinetics in Patients with Moderately to Severely Active Ulcerative Colitis: Results from Phase III LUCENT Studies.

Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis. Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations. Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%. Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required. ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).

Isavuconazole Exposure in Critically Ill Patients Treated with Extracorporeal Membrane Oxygenation: Two Case Reports and a Narrative Literature Review.

Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxygenation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacokinetic data in patients supported by ECMO are limited. Therefore, it is unknown whether ECMO independently impacts isavuconazole exposure. We measured isavuconazole plasma concentrations in two patients supported by ECMO and estimated individual pharmacokinetic parameters using non-compartmental analysis and two previously published population pharmacokinetic models. Furthermore, a narrative literature review on isavuconazole exposure in adult patients receiving ECMO was performed. The 24 h areas under the concentration-time curve and trough concentrations of isavuconazole were lower in both patients compared with exposure values published before. In the literature, highly variable isavuconazole concentrations have been documented in patients with ECMO support. The independent effect of ECMO versus critical illness itself on isavuconazole exposure cannot be deduced from our and previously published (case) reports. Pending additional data, therapeutic drug monitoring is recommended in critically ill patients, regardless of ECMO support.

Is age just a number? A population pharmacokinetic study of gemcitabine

Pharmacokinetic exposure to gemcitabine and its metabolite, 2',2'-difluorodeoxyuridine (dFdU), might be altered in elderly compared to their younger counterparts. It is unknown if age-based dose adjustments are necessary to reduce the development of treatment-induced adverse events. The aim of this study was to assess the impact of age on the pharmacokinetics of gemcitabine and dFdU. Pharmacokinetic sampling following a flexible limited sampling strategy was performed in patients ≥ 70years after gemcitabine infusion. The data were supplemented with pharmacokinetic data in patients included in four previously conducted clinical trials. Nonlinear mixed effects modelling was performed on the pooled dataset to assess the impact of age on the pharmacokinetics of gemcitabine and dFdU. In total, pharmacokinetic data were available of 197 patients, of whom 83 patients were aged ≥ 70years (42%). A two-compartment model for both gemcitabine and dFdU with linear clearances from the central compartments described the data best. Age, tested as continuous and categorical (< 70years versus ≥ 70years) covariate, did not statistically affect the pharmacokinetics of gemcitabine and dFdU. Age was not of influence on the pharmacokinetics of gemcitabine or its metabolite, dFdU. Age-related dose adjustments for gemcitabine based on pharmacokinetic considerations are not recommended. NL39647.048.12, registered on May 3rd 2012.

Subcutaneous Infliximab, CT-P13SC: A Profile of Its Use in the EU.

CT-P13 (Remsima®; Inflectra®), a biosimilar of reference infliximab (Remicade®), provides a useful alternative for patients requiring infliximab therapy and, as with other biosimilar agents, has the potential to reduce treatment costs. Furthermore, the availability of CT-P13 in a subcutaneous formulation (CT-P13SC), with the possibility (after adequate training) of self-administration at home, has the potential to both improve patient convenience and reduce the burden on the healthcare system. The initial approval of CT-P13SC, for use in the treatment of rheumatoid arthritis in adults, was based on the findings of a randomised, double-blind phase I/III trial which demonstrated the non-inferiority of CT-P13SC administered once every 2weeks to intravenous CT-P13 (CT-P13IV) administered once every 8weeks in reducing disease activity in patients with active rheumatoid arthritis. Subsequently, based on pharmacokinetic data in patients with inflammatory bowel disease, CT-P13SC has also been approved in the EU for use in the treatment of Crohn's disease, ulcerative colitis and, by extrapolation, ankylosing spondylitis, psoriatic arthritis and psoriasis, in adults.

Comprehensive PBPK model to predict drug interaction potential of Zanubrutinib as a victim or perpetrator.

A physiologically based pharmacokinetic (PBPK) model was developed to evaluate and predict (1) the effect of concomitant cytochrome P450 3A (CYP3A) inhibitors or inducers on the exposures of zanubrutinib, (2) the effect of zanubrutinib on the exposures of CYP3A4, CYP2C8, and CYP2B6 substrates, and (3) the impact of gastric pH changes on the pharmacokinetics of zanubrutinib. The model was developed based on physicochemical and in vitro parameters, as well as clinical data, including pharmacokinetic data in patients with B‐cell malignancies and in healthy volunteers from two clinical drug‐drug interaction (DDI) studies of zanubrutinib as a victim of CYP modulators (itraconazole, rifampicin) or a perpetrator (midazolam). This PBPK model was successfully validated to describe the observed plasma concentrations and clinical DDIs of zanubrutinib. Model predictions were generally within 1.5‐fold of the observed clinical data. The PBPK model was used to predict untested clinical scenarios; these simulations indicated that strong, moderate, and mild CYP3A inhibitors may increase zanubrutinib exposures by approximately four‐fold, two‐ to three‐fold, and <1.5‐fold, respectively. Strong and moderate CYP3A inducers may decrease zanubrutinib exposures by two‐ to three‐fold or greater. The PBPK simulations showed that clinically relevant concentrations of zanubrutinib, as a DDI perpetrator, would have no or limited impact on the enzyme activity of CYP2B6 and CYP2C8. Simulations indicated that zanubrutinib exposures are not impacted by acid‐reducing agents. Development of a PBPK model for zanubrutinib as a DDI victim and perpetrator in parallel can increase confidence in PBPK models supporting zanubrutinib label dose recommendations.

Pharmacokinetics of culture-directed antibiotics for the treatment of peritonitis in automated peritoneal dialysis: A systematic narrative review.

The objectives of this study were to provide a summary of the pharmacokinetic data of some intraperitoneal (IP) antibiotics that could be used for both empirical and culture-directed therapy, as per the ISPD recommendations, and examine factors to consider when using IP antibiotics for the management of automated peritoneal dialysis (APD)-associated peritonitis. A literature search of PubMed, EMBASE, Scopus, MEDLINE and Google Scholar for articles published between 1998 and 2020 was conducted. To be eligible, articles had to describe the use of antibiotics via the IP route in adult patients ≥18 years old on APD in the context of pharmacokinetic studies or case reports/series. Articles describing the use of IP antibiotics that had been recently reviewed (cefazolin, vancomycin, gentamicin and ceftazidime) or administered for non-APD-associated peritonitis were excluded. A total of 1119 articles were identified, of which 983 abstracts were screened. Seventy-three full-text articles were assessed for eligibility. Eight records were included in the final study. Three reports had pharmacokinetic data in patients on APD without peritonitis. Each of cefepime 15 mg/kg IP, meropenem 0.5 g IP and fosfomycin 4 g IP given in single doses achieved drug plasma concentrations above the minimum inhibitory concentration for treating the susceptible organisms. The remaining five records were case series or reports in patients on APD with peritonitis. While pharmacokinetic data support intermittent cefepime 15 mg/kg IP daily, only meropenem 0.5 g IP and fosfomycin 4 g IP are likely to be effective if given in APD exchanges with dwell times of 15 h. Higher doses may be required in APD with shorter dwell times. Information on therapeutic efficacy was derived from case reports/series in individual patients and without therapeutic drug monitoring. Until more pharmacokinetic data are available on these antibiotics, it would be prudent to shift patients who develop peritonitis on APD to continuous ambulatory peritoneal dialysis, where pharmacokinetic information is more readily available.

Systemic and Target-Site Pharmacokinetics of Antiparasitic Agents.

About one-sixth of the world’s population is affected by a neglected tropical disease as defined by the World Health Organization and Center for Disease Control. Parasitic diseases comprise most of the neglected tropical disease list and they are causing enormous amounts of disability, morbidity, mortality, and healthcare costs worldwide. The burden of disease of the top five parasitic diseases has been estimated to amount to a total 23 million disability-adjusted life-years. Despite the massive health and economic impact, most drugs currently used for the treatment of parasitic diseases have been developed decades ago and insufficient novel drugs are being developed. The current review provides a compilation of the systemic and target-site pharmacokinetics of established antiparasitic drugs. Knowledge of the pharmacokinetic profile of drugs allows for the examination and possibly optimization of existing dosing schemes. Many symptoms of parasitic diseases are caused by parasites residing in different host tissues. Penetration of the antiparasitic drug into these tissues, the target site of infection, is a prerequisite for a successful treatment of the disease. Therefore, for the examination and improvement of established dosing regimens, not only the plasma but also the tissue pharmacokinetics of the drug have to be considered. For the current paper, almost 7000 scientific articles were identified and screened from which 429 were reviewed in detail and 100 were included in this paper. Systemic pharmacokinetics are available for most antiparasitic drugs but in many cases, not for all the relevant patient populations and only for single- or multiple-dose administration. Systemic pharmacokinetic data in patients with organ impairment and target-site pharmacokinetic data for relevant tissues and body fluids are mostly lacking. To improve the treatment of patients with parasitic diseases, research in these areas is urgently needed.

Clinical Pharmacometrics for Rational Drug Treatment

Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.

Vancomycin Removal During High-Volume Peritoneal Dialysis in Acute Kidney Injury Patients: A Prospective Cohort Clinical Study

IntroductionVancomycin pharmacokinetic data in patients with acute kidney injury (AKI) on high-volume peritoneal dialysis (HVPD) are lacking. The aims were to study the pharmacokinetics of i.v. vancomycin in patients with AKI treated by HVPD who received an i.v. dose of vancomycin (15–20 mg/kg), to determine the vancomycin removal, and to establish vancomycin dosing and evaluation pharmacokinetics target attainment achievement for the empirical treatment of patients with AKI treated by HVPD.MethodsVancomycin was administered 1 hour before dialysis start. Samples of all dialysate were collected for a 24-hour period. Blood samples were collected after 1, 2, 4, and 24 hours of therapy. Vancomycin concentrations were determined using a liquid chromatographic (high-performance liquid chromatography)–fluorescence method. Pharmacokinetic calculations were completed assuming a 1-compartment model.ResultsTen patients completed the study. The mean vancomycin dose administered was 18.0 ± 2.95 mg/kg (14.7–21.8 mg/kg) on the day of study (first day) and the mean percentage of vancomycin removal by HVPD was 21.7% ± 2.2% (16%–29%). Peritoneal clearance was 8.1 ± 2.2 ml/min (5.3–12 ml/min). The serum vancomycin half-life was 71.2 ± 24.7 hours (42–110 hours) during HVPD session, the maximum serum concentration was 26.2 ± 3.5 mg/l, which occurred 1 hour after vancomycin administration and HVPD start. Area under the curve (AUC)0–24/minimum inhibitory concentration (MIC) ratio ≥400 was achieved in all patients when MIC = 1 mg/l was considered.ConclusionHVPD removes considerable amounts of vancomycin in septic patients with AKI. Administration of 18 mg/kg vancomycin each 48 to 72 hours in patients with AKI undergoing HVPD was required to reach and maintain therapeutic concentrations.

Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study.

BackgroundVentriculitis is a complication of temporary intraventricular drains. The limited penetration of meropenem into the cerebrospinal fluid (CSF) is well known. However, ventricular CSF pharmacokinetic data in patients with ventriculitis are lacking. The aim of this study was to evaluate meropenem pharmacokinetics in the serum and CSF of neurocritical care patients with proven or suspected ventriculitis.MethodsWe conducted an observational pharmacokinetic study of neurocritical care patients with proven or suspected ventriculitis receiving meropenem. Multiple blood and CSF samples were taken and were described using nonparametric pharmacokinetic modelling with Pmetrics.ResultsIn total, 21 patients (median age 52 years, median weight 76 kg) were included. The median (range) of peak and trough concentrations in serum were 20.16 (4.40–69.00) mg/L and 2.54 (0.00–31.40) mg/L, respectively. The corresponding peak and trough concentrations in CSF were 1.20 (0.00–6.20) mg/L and 1.28 (0.00–4.10) mg/L, respectively, with a median CSF/serum ratio (range) of 0.09 (0.03–0.16). Median creatinine clearance ranged from 60.7 to 217.6 ml/minute (median 122.5 ml/minute). A three-compartment linear population pharmacokinetic model was most appropriate. No covariate relationships could be supported for any of the model parameters. Meropenem demonstrated poor penetration into CSF, with a median CSF/serum ratio of 9 % and high interindividual pharmacokinetic variability.ConclusionsAdministration of higher-than-standard doses of meropenem and therapeutic drug monitoring in both serum and CSF should be considered to individualise meropenem dosing in neurocritical care patients with ventriculitis.

Analysis of clinical trials of biosimilar infliximab (CT-P13) and comparison against historical clinical studies with the infliximab reference medicinal product

Objective: To examine whether efficacy, safety and pharmacokinetic (PK) data observed with CT-P13 (Remsima®; Inflectra®), an infliximab biosimilar, are similar to those from published reports with the reference medicinal product (RMP; Remicade®) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS). Methods: Literature searches were performed to identify clinical studies with infliximab RMP. Efficacy, safety and PK data were indirectly compared with data from head-to-head clinical trials of CT-P13 and RMP. Results: CT-P13 and RMP produce similar efficacy in patients with RA and AS when compared across clinical studies. There are no substantial differences in the incidence of infusion-related reactions, infections, serious infections, malignancy or lymphoma. PK data in patients with RA are similar in direct comparisons and comparisons with historical data. Conclusion: Efficacy, safety and PK data are highly comparable between CT-P13 and RMP, both in head-to-head clinical studies, and indirect comparisons with historical clinical data for RMP.

Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type2 diabetes mellitus.

Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

Pharmacokinetic predictions for patients with renal impairment: focus on peptides and protein drugs

• Renal impairment may affect the pharmacokinetics of peptide and protein drugs. • Molecular size is a predictor. Small molecules are eliminated by the kidneys, whereas large molecules (>67 kDa) are not. • Urinary recovery of peptide and protein drugs in healthy volunteers is not predictive for pharmacokinetic changes in patients with renal impairment. • An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations as observed in patients with severe renal impairment or end-stage renal disease is described. • Potentially relevant pharmacokinetic changes were found for drugs with a molecular weight below 50 kDa. • Analysis of observed pharmacokinetics in patients with severe renal impairment may be a useful approach, especially when urinary recovery in healthy volunteers is not predictive. Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived. Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid E(max) model was applied and fitted to the data and the prediction error was analyzed. Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life). An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients.

Drug Interaction Studies: Study Design, Data Analysis, and Implications for Dosing and Labeling

One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose-response studies, and drug-drug interactions.

Pharmacokinetics of Oral Ciprofloxacin in Continuous Cycling Peritoneal Dialysis

In order to avoid aminoglycosides, the International Society for Peritoneal Dialysis recommends cefazolin and ceftazidime for empirical treatment of peritonitis. Ciprofloxacin covers relevant gram-negative pathogens without the resistance associated with ceftazidime. However, ciprofloxacin pharmacokinetic data in patients on continuous cycling peritoneal dialysis (CCPD) are lacking. (1) To determine the pharmacokinetics of oral ciprofloxacin in CCPD patients, (2) to compare serum and dialysate ciprofloxacin concentrations with minimum inhibitory concentrations (MIC) of the gram-negative bacteria associated with peritonitis, and (3) to establish oral ciprofloxacin dosing guidelines for the empirical treatment of peritonitis in patients receiving CCPD. Eligible CCPD patients received 2 doses of ciprofloxacin: 750 mg orally every 12 hours. Serial blood and end-of-dwell dialysate samples were collected during the first 12-hour interval; an end-of-dwell dialysate sample from the overnight dwell and a final blood sample were collected at the end of the second 12-hour interval. Ciprofloxacin concentrations were determined using a liquid chromatographic (HPLC)-fluorescence method. Pharmacokinetic calculations were completed assuming a one-compartment model. Eight patients completed the study. The pharmacokinetic parameters determined for ciprofloxacin were (mean +/- SEM) serum half-life 10.1 +/- 1.2 hours, maximum serum concentration 2.7 +/- 0.5 mg/L, time to maximum serum concentration 1.6 +/- 0.1 hours after the first dose, and peritoneal clearance 1.2% +/- 0.1% of the mean calculated total body clearance. While all patients achieved serum area under the concentration-time curve:MIC > 125 for Escherichia coli and Klebsiella species after the first dose, only 2 patients achieved this goal for Pseudomonas aeruginosa. End-of-dwell dialysate concentrations were above the MIC for E. coli, Klebsiella spp, and P. aeruginosa after the second dose. Ciprofloxacin 750 mg orally every 12 hours in CCPD patients may be useful for empirical gram-negative coverage of CCPD peritonitis and for treatment of documented peritonitis caused by sensitive E. coli or Klebsiella species. While ceftazidime may be required for documented pseudomonal peritonitis, the oral ciprofloxacin regimen achieved adequate serum concentrations to treat systemic gram-negative infections caused by sensitive E. coli or Klebsiella species.

Comparative effects of rifabutin and rifampicin on cytochromes P450 and UDP-glucuronosyl-transferases expression in fresh and cryopreserved human hepatocytes

The aim of this study was to evaluate rifabutin (RBT) and rifampicin (RIF) capabilities in inducing various xenobiotic metabolizing enzymes such as cytochromes P450 (CYPs) and UDP-glucuronosyl-transferases (UGTs) in cultured fresh and cryopreserved human hepatocytes. Enzyme induction was assessed through the use of several diagnostic markers, i.e. testosterone, midazolam (MDZ), diazepam (DZP) and 7-ethoxyresorufin for CYP-dependent enzyme reactions; and AZT for UGT-dependent enzyme reactions. RBT concentrations (0.118, 0.708 μM) were selected according to previously published pharmacokinetic data in patients. The known CYP3A4 inducer in humans, RIF, was used as a positive control. At the concentrations used, no sign of cytotoxicity was evidenced. Both compounds were able to dose-dependently induce the overall metabolism of testosterone (∼2-fold for RBT, ∼4-fold for RIF) and the formation of the 6β-hydroxylated-derivative (up to ∼4-fold over control for RBT and ∼10-fold for RIF), which is CYP3A4 dependent. The other hydroxylated metabolites (16α-OH and 2α-OH) were also enhanced. The metabolism of MDZ, which is specifically metabolized by CYP3A4 in humans, was also investigated following drug's exposure to hepatocytes. DZP one, which is governed by various CYPs, including CYP3A, was also investigated. RBT was shown to increase the biotransformation of both benzodiazepines (∼1.9-fold over control). Moreover, the effects of both drugs on ethoxyresorufin O-deethylase activity (EROD), which is representative of CYP1A1/2 isoforms, were tested. Results showed only a moderate induction of this marker (∼2-fold over control) when compared to the high effect observed after hepatocyte exposure to 3-methylcholantene (∼14-fold over control). Finally, the action of RBT and RIF on UGTs expression was investigated by using AZT as diagnostic substrate: glucuronides formation was not significantly affected by the two rifamycin derivatives. On the whole, exposure of fresh or cryopreserved human hepatocytes to RBT dose-dependently affected the levels of drug metabolizing enzymes in a dose-dependent manner. However, as already demonstrated by in vivo pharmacokinetic studies, its inducing properties towards CYPs, CYP3A in particular, are less pronounced than RIF.

Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer

Treatment of superficial bladder cancers by intravesical mitomycin C (MMC) chemotherapy gives a varying and incomplete response. Our recent pharmacokinetics and pharmacodynamics studies have shown that treatment effectiveness is limited by drug degradation in acidic urine and by drug dilution due to residual urine volume and urine production. A model was developed to predict drug exposure in tumors in the bladder wall and to correlate drug exposure with antitumor effect. The model is based on the known pharmacokinetic data in patients treated with intravesical chemotherapy, drug-penetration data in the bladder wall of patients undergoing radical cystectomy, and pharmacodynamic data on patients' bladder-tumor chemosensitivity. Computer simulations based on the model were generated. The simulations predicted that changes in treatment parameters would affect the therapeutic outcome in the following rank order: dose > residual volume > urine production > dosing volume > urine pH > dwell time. Tissue exposure could be enhanced by increased dose, complete bladder emptying, reduced fluid intake, use of the minimal dosing volume, and alkalinization of the urine to a neutral pH. Increasing the dwell time from 2 to 4 h gave an insignificant improvement and posed a compliance problem. The selected optimized regimen of a 40-mg dose, no residual volume, 0.62-ml/min urine production, a 20-ml dosing volume, and alkaline urine pH yielded a calculated 8.5-fold increase in tissue exposure over that achieved by the standard regimen, which consisted of a 20-mg dose, 32-ml residual volume, 1.5-ml/min urine production, a 20-ml dosing volume, and acidic urine pH. On the basis of previously established pharmacodynamic data, we hypothesize that the increase in tissue exposure in the optimized treatment would result in a 20% improvement over the standard therapy along with an increase in the recurrence-free rate from 56% to 76% of patients. A phase III efficacy trial comparing the optimized and standard regimens is proposed.

A new extra long acting depot preparation of the LHRH analogue Zoladex®. First endocrinological and pharmacokinetic data in patients with advanced prostate cancer

A new depot formulation of the LHRH analogue Zoladex® (goserelin acetate) has been developed which releases the drug over a period of at least 3 months as judged by measurement of drug content in depots at intervals after insertion in male rats and by the suppression of oestrogen secretion and oestrus in female rats. This formulation is based on the lactide/glycolide polymer system used for the standard 1-month Zoladex® depot, but the dose has been increased to 10.8 mg and the characteristics have been modified to enable a longer release of drug to be achieved. Thirty-eight patients with histologically proven, locally advanced (stage T3 or T4) and/or metastatic prostate cancer were treated with this new longer acting LHRH analogue depot formulation containing 10.8 mg Zoladex®. After initial increase of serum testosterone in the first week of therapy, castration levels were reached in all patients after 4 weeks and this was maintained for more than 14 weeks. At the time of depot exhaustion, when escape from castration levels of androgen occurred, all patients received a single injection of a standard 1-month depot containing 3.6 mg Zoladex® which restored castration levels of androgen thus showing that the pituitary gland was again suppressed. The tolerance and acceptability of the longer-acting depot is high and comparable to the 1-month depot. Taking into account social and psychological factors, patients with advanced prostate carcinoma will soon be able to be treated with a longer acting LHRH depot formulation every 3 months an alternative of the 1-month depot now widely used clinically.

Comparison of Two Infusion Methods for Pharmacokinetic Monitoring of Gentamicin

Gentamicin is commonly administered by intermittent infusions using a gravity-flow or a mechanical device. The primary objective of our study was to compare the pharmacokinetic data in patients receiving gentamicin infusion by a syringe pump and a new controlled-release membrane infusion device. The membrane device consists of a drug and a fluid chamber separated by a 0.2-micron proprietary membrane; drug transfer is based on electrodiffusion across the membrane. Ten patients (mean age 50 years) received the same dose of gentamicin, separated by a 24-h interval, from two devices. Differences in serum concentrations, distribution volume, and half-life were not statistically significant. However, time for complete delivery (0.9 +/- 0.4 h for membrane device vs. 0.5 h for syringe pump) and calculated dosage requirements (10.9 +/- 6.3 vs. 9.6 +/- 5.5 mg/h) to achieve peak of 7 and trough of 1 microgram/ml were significantly different (p less than 0.05). Thus, the infusion method for gentamicin can have a significant influence on its pharmacokinetic monitoring.

Oral pharmacokinetics of felodipine in patients with congestive heart failure: variable prediction using intravenous data.

Peak and trough concentrations after 8 weeks oral therapy with felodipine, a vasodilating calcium antagonist of the dihydropyridine group, were predicted from intravenous pharmacokinetic data before therapy in 11 patients, randomly allocated to felodipine treatment 10 mg b.i.d., during a placebo controlled study in patients with congestive heart failure. Peak concentrations were well predictable, but trough levels varied between a good agreement in some patients to a large underestimation in others. Predictability was significantly correlated with half life, plasma clearance and distribution volume of the intravenous pharmacokinetic study. After 8 weeks chronic oral therapy no significant differences could be detected between the oral pharmacokinetics of predictable (n = 6) and unpredictable (n = 5) patients. This demonstrates that felodipine kinetics change during felodipine treatment. Differences in the distribution of blood flow before therapy combined with an interindividual variability in blood flow response during therapy is probably responsible for the observed impossibility to calculate trough levels, and thus oral dosage schedules, from intravenous pharmacokinetic data in patients with congestive heart failure.