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Insights from modeling and simulation (M&S) can help to overcome critical challenges associated with oncology clinical trials, by quantitatively integrating knowledge and relationships between the disease, drug characteristics, patient populations, [...]

ObjectivesIntranasal nalbuphine could be a safe, efficacious and non-invasive alternative to parenteral pain medication in infants. We aimed to assess pharmacokinetics (PK) and tolerability of intranasal and intravenous nalbuphine administration in infants.MethodsProspective open-label study including infants 1–3 months of age admitted to the emergency department, receiving nalbuphine for procedural pain management. Patients were alternately allocated to a single nalbuphine dose of 0.05 mg/kg intravenously or 0.1 mg/kg intranasally. Nalbuphine PK samples were collected 15, 30 and 120–180 min after dosing. Area under the concentration time curve (AUC0-Tlast) was calculated by non-compartmental analysis (NCA) and compared by Wilcoxon test. Neonatal Infant Pain Score was assessed during nalbuphine administration and the following interventions: venous access, urinary catheterisation, lumbar puncture.ResultsOut of 52 study subjects receiving nalbuphine, 31 were eligible for NCA (11 intravenous, 20 intranasal). Median AUC0-Tlastafter 0.05 mg/kg intravenously was 8.7 (IQR: 8.0–18.6) µg×L/hour vs 7.6 (5.4–10.4) µg×L/hour after intranasal administration of 0.1 mg/kg (p=0.091). Maximum serum concentration (Cmax) was observed 30 min after intranasal administration (3.5–5.6 µg/L). During intravenous and intranasal nalbuphine administration, mild to no pain was recorded in 71% and 67% of study subjects, respectively.ConclusionThis is the first study investigating intranasal administration of nalbuphine in infants suggesting an intranasal bioavailability close to 50%. Non-invasive intranasal application was well tolerated. Additional studies are warranted to optimise dosing and timing of interventions as Cmaxis delayed by half an hour after intranasal administration.Trial registration numberNCT03059511.

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: −0.03%[−0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[−1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment.

OBJECTIVE--To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [[T.sub.mG]], increased splay, and [...]

ObjectiveExploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates.DesignProspective, single-centre, open-label, pharmacokinetics study in preterm neonates.SettingNeonatal intensive care unit at McMaster Children’s Hospital.PatientsNeonates with a gestational age ≤28+6weeks treated with oral ibuprofen for closure of a PDA.MethodsPopulation pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation.Main outcome measureAssociation between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0–72h>900 mg·hour/L).ResultsTwenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0–72hwas observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure.ConclusionWe designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0–72h>900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

The indicated dose of 4-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with an international normalized ratio (INR) of 2 to 4 is 25 IU/kg, but there is no indicated dose for INR <2. We explored 4F-PCC dosing strategies for baseline INR <2. Clinical trial data were used to develop pharmacometric models for Factor X (FX) and FII, accounting for covariates including baseline INR. FX and FII levels over time were simulated for mean baseline INR levels of the clinical trial participants plus baseline INRs 3.1, 1.9, and 1.6. For each INR, 200 virtual male patients were simulated to evaluate 4F-PCC doses of 35, 25, 20, 15, 12.5, and 10 IU/kg. Given an elevated bleeding risk with VKA therapy in Japanese vs Western populations, results were stratified by Japanese and non-Japanese patients. Target levels of FX and FII were ≥50% activity at 30 minutes after dosing in ≥80% of patients. FX- and FII-time models were developed with 1088 FX observations from 193 patients and 1074 FII observations from 192 patients. Model-based simulations indicated that at baseline INR 3.1, ≥80% of patients achieved ≥50% FX and FII activity with 25 IU/kg and 20 IU/kg 4F-PCC, respectively; at baseline INR 1.9, corresponding doses were 20 IU/kg and 15 IU/kg 4F-PCC, and at baseline INR 1.6, corresponding doses were 15 IU/kg, and 10 IU/kg 4F-PCC. Trends in Japanese and non-Japanese patients were similar. In conclusion, low 4F-PCC doses (15-20 IU/kg) may be sufficient to achieve hemostatic levels of FX and FII in Japanese and non-Japanese patients with baseline INR <2.

Supplemental Digital Content is available in the text.Urea dialyzer clearance (KD) has been suggested to be underpredicted from blood flow (QB), dialysate flow (QD), and in vitromass transfer-area coefficient of urea (KoA) in pediatric hemodialysis (HD) patients using a widely accepted mechanistic equation. We characterize factors that could explain this, assuming that it results from a bias between reported in vitroand actual in vivoKoA. An adult urea kinetic model was scaled to 923 patients aged 1–29 years based on pediatric physiologic knowledge (intercompartmental clearance, volumes of distribution). Using data from 2,676 HD sessions of those patients (pre-/post-HD urea concentrations and HD treatment parameters), mixed effect modeling was applied to estimate individual KoA correction factors (fKoA) required for unbiased KDand post-HD urea concentration predictions in vivo. QD/QBratio was most strongly associated with individual fKoAestimates (P< 0.001; fKoA= −1%, 18%, and 110% at QD/QBratios of 1.5, 2, and 5). Additional factors included in the model were filter flux (−12% lower fKoAfor low- vs high-flux filters), ultra-filtration rate, and true QB(lower than nominal QB≥200 ml/min). Of note, high QD/QBratios used in children ≤6 years were associated with significant underprediction of KDin vivo, with post-HD urea concentrations being 23% lower than expected. In conclusion, dialyzers should be characterized under pediatric conditions where high QD/QBratios are used. Our model can be used to prevent underestimation of urea clearance, allowing shorter dialysis sessions, higher quality of life, and individualized treatment prescription in children on maintenance HD.

Copeptin is the C-terminal fragment of the arginine vasopressin (AVP) prohormone whose measurement is more robust than that of AVP. Similar release and clearance characteristics have been suggested promoting copeptin as a surrogate marker.

ABSTRACTIntroduction: For safe and effective neonatal antibiotic therapy, knowledge of the pharmacokinetic parameters of antibacterial agents in neonates is a prerequisite. Fast maturational changes during the neonatal period influence pharmacokinetic and pharmacodynamic parameters and their variability. Consequently, the need for applying quantitative clinical pharmacology and determining optimal drug dosing regimens in neonates has become increasingly recognized.Areas covered: Modern quantitative approaches, such as pharmacometrics, are increasingly utilized to characterize, understand and predict the pharmacokinetics of a drug and its effect, and to quantify the variability in the neonatal population. Individual factors, called covariates in modeling, are integrated in such approaches to explain inter-individual pharmacokinetic variability. Pharmacometrics has been shown to be a relevant tool to evaluate, optimize and individualize drug dosing regimens.Expert opinion: Challenges for optimal use of antibiotics in neonates can largely be overcome with quantitative clinical pharmacology practice. Clinicians should be aware that there is a next step to support the clinical decision-making based on clinical characteristics and therapeutic drug monitoring, through Bayesian-based modeling and simulation methods. Pharmacometric modeling and simulation approaches permit us to characterize population average, inter-subject and intra-subject variability of pharmacokinetic parameters such as clearance and volume of distribution, and to identify and quantify key factors that influence the pharmacokinetic behavior of antibiotics during the neonatal period.

Zusammenfassung.Entwicklungsbedingte physiologisch-pharmakologische Faktoren beeinflussen das Nebenwirkungsprofil von Arzneimitteln (unerwünschte Arzneimittelwirkungen, UAW) in der Kindheit. Eine erhöhte Empfindlichkeit gegenüber UAW wird vor allem bei Säuglingen und Neugeborenen beobachtet, verursacht durch eine grössere Arzneimittel-Exposition (aufgrund veränderter Pharmakokinetik) oder eine grössere Empfindlichkeit gegenüber dem Arzneimittel (aufgrund veränderter Pharmakodynamik). Das Wirkungs- und Nebenwirkungsprofil der meisten erhältlichen Arzneimittel wurde bei Kindern nicht formell in klinischen Studien evaluiert. Daher ist die optimale Dosierung bei dieser Patientengruppe selten bekannt. Zudem erschweren kinderunfreundliche Arzneiformen eine exakte Dosierung, was das Risiko von UAW aufgrund eines Dosierungsfehlers erhöht. Dieser Artikel gibt einen Überblick über pädiatrische UAW und zeigt neue Entwicklungen im regulatorischen und pharmakologisch-klinischen Bereich auf, die zukünftig helfen könnten, unerwünschte Nebenwirkungen bei Kindern besser zu verstehen und vermeiden.

Standard treatment for patients with primary immunodeficiency (PID) is monthly intravenous immunoglobulin (IVIG), or weekly/biweekly subcutaneous immunoglobulin (SCIG) infusion. We used population pharmacokinetic modeling to predict immunoglobulin G (IgG) exposure following a broad range of SCIG dosing regimens for initiation and maintenance therapy in patients with PID. Simulations of SCIG dosing were performed to predict IgG concentration–time profiles and exposure metrics [steady-state area under the IgG concentration–time curve (AUC), IgG peak concentration (Cmax), and IgG trough concentration (Cmin) ratios] for various infusion regimens. The equivalent of a weekly SCIG maintenance dose administered one, two, three, five, or seven times per week, or biweekly produced overlapping steady-state concentration–time profiles and similar AUC, Cmax, and Cminvalues [95% confidence interval (CI) for ratios was 0.98–1.03, 0.95–1.09, and 0.92–1.08, respectively]. Administration every 3 or 4 weeks resulted in higher peaks and lower troughs; the 95% CI of the AUC, Cmax, and Cminratios was 0.97–1.04, 1.07–1.26, and 0.86–0.95, respectively. IgG levels >7 g/L were reached within 1 week using a loading dose regimen in which the weekly maintenance dose was administered five times in the first week of treatment. In patients with very low endogenous IgG levels, administering 1.5 times the weekly maintenance dose five times in the first week of treatment resulted in a similar response. The same total weekly SCIG dose can be administered at different intervals, from daily to biweekly, with minimal impact on serum IgG levels. Several SCIG loading regimens rapidly achieve adequate serum IgG levels in treatment-naïve patients.

ABSTRACTAtazanavir (Reyataz; ATV) is a well-tolerated protease inhibitor (PI) that is indicated as a once-daily treatment for HIV infections. These features of ATV, combined with its virologic potency, make it particularly desirable for the treatment of HIV-infected pediatric patients. The objective of this study was to use a model-based approach to recommend body weight-based ATV capsule doses for pediatric patients. ATV concentration-time data from three adult studies and one pediatric study were described by a C0-delinked one-compartment model to guard against introducing bias in pharmacokinetic (PK) parameter estimates due to the potential nonadherence in outpatient studies. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were determined to increase with body weight, and CL/Fwas 40.9% lower in patients receiving ATV comedication with ritonavir (RTV). The relative bioavailability (Frel) of ATV was 132% higher with RTV comedication and was 35.5% lower for the ATV powder formulation than the capsule formulation. Model-based simulations were used to recommend weight-based ATV capsule doses of 150 to 300 mg boosted with 100 mg RTV for pediatric patients weighing ≥15 kg, such that the exposures in these patients are similar to those obtained in HIV-infected adults treated with the recommended ATV/RTV dose of 300/100 mg.

Incorporating urea rebound using equilibrated urea concentration (Ceq) after hemodialysis (HD) is essential for accurate assessment of HD efficiency. It is impractical to measure Ceqin clinical settings, and there are no recommended methodologies to predict Ceqin children. The objective of this work is to assess the ability of an Individualized Bayesian Urea Kinetic Model (IBKM) for predicting Ceqin children receiving HD. Developed based on adult HD data, the IBKM is a two-pool urea kinetic model that calculates Bayesian estimates of individual Ceq. Blood urea nitrogen (BUN) samples from 30 HD sessions in 13 children (age 12–18 years) were taken at pre-HD, immediately post-HD, and 60 minutes post-HD (Ceq). The IBKM and estimated population parameters from adult data were fitted to the observed data from children to predict individual Cequsing NONMEM VI software in comparison with observed Ceq(9.5 ± 3.8 mmol/L), the average individual predicted Ceqwas 9.4 ± 3.8 mmol/L, with absolute individual prediction error of 6.2% ± 4.4%. For a given dialysis goal and desired dialysis duration, the required blood flow rate and dialyzer size are predicted by IBKM and confirmed by the analysis data. This study suggests that the IBKM can be used in a pediatric HD setting and accurately predict Ceqin children using only pre-HD and immediately post-HD BUN.

Importance of the field:Current drug discovery and development programs are under growing scrutiny for low productivity and escalating costs. Model-based drug development (MBDD) has been recognized as a promising tool to address some of the related challenges.Areas covered in this review:This review introduces the concept of MBDD and the associated quantitative pharmacology-based iterative ‘‘learn and confirm’’ paradigm in the drug discovery and development process to provide concise information for rational decision making. It summarizes the evolving role of MBDD in drug development programs and outlines the full armamentarium of modeling and simulation approaches utilized to facilitate its application.What the reader will gain:Different aspects and applications of MBDD are introduced to the reader and illustrated in prime examples. The reader is provided with an understanding of potential applications of MBDD in drug development as well as the associated limitations and challenges in its implementation.Take home message:MBDD is a tool that is increasingly used throughout the drug discovery and development continuum to support fast and rationale decision making and has thereby the potential to accelerate and increase the cost-effectiveness of the drug development process.

ABSTRACTCharacterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.

ABSTRACTEntecavir is a guanosine nucleoside analogue approved for the treatment of chronic hepatitis B virus (HBV) infection. The impact of human immunodeficiency virus (HIV) coinfection on the pharmacokinetics (PK) of entecavir was examined by nonlinear mixed-effects modeling. Plasma concentration data from HIV- and HBV-coinfected patients were analyzed in conjunction with data from HBV-monoinfected patients, and HIV coinfection was tested as a covariate on oral clearance (CL/F). The estimated population averages of intercompartmental clearance and the volumes of distribution in the central and peripheral compartments obtained with a 1-mg dose were 34.2 liters/h (interindividual variability, 30.2%), 115 liters (interindividual variability, 39.2%), and 1,830 liters (interindividual variability, 74%), respectively. CL/Fwas found to be a function of creatinine clearance, but HIV confection did not show any effect on CL/F. The geometric mean (GM) of individual Bayesian estimates of the steady-state area under the concentration-time curve following 1-mg daily doses were 39.3 and 38.8 ng·h/ml in HIV- and HBV-coinfected and HBV-monoinfected patients, respectively. The adjusted GM ratio (1.01; 90% confidence interval, 0.91 to 1.12) was within the bioequivalence criteria boundary (0.80 to 1.25). In conclusion, the proposed model adequately described the entecavir PK in HBV- and HIV-coinfected patients and HBV-monoinfected patients, and the entecavir exposures were comparable in the two patient populations.

ABSTRACTThe penetration of daptomycin, a new lipopeptide antibiotic, into inflamed meninges ranged between 4.37 and 7.53% (mean, 5.97%). Daptomycin was very efficacious in the treatment of experimental pneumococcal meningitis, producing a decrease of −1.20 ± 0.32 Δlog10CFU/ml · h in the bacterial titer of Streptococcus pneumoniaeagainst a penicillin-resistant strain and of −0.97 ± 0.32 Δlog10CFU/ml · h against a penicillin- and quinolone-resistant strain found in cerebrospinal fluid (CSF). For both strains, daptomycin was significantly superior to the standard regimen of a combination of ceftriaxone with vancomycin, sterilizing 9 of 10 CSF samples after 4 h. In vitro, daptomycin produced highly bactericidal activity in concentrations above the MIC.

Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin‐converting enzyme (ACE) has gained increasing interest in the treatment of hypertension, heart failure, and renoprotection. Specifically, M100240, the thioester of the dual ACE/NEP inhibitor MDL100,173, has been evaluated in the management of hypertension. A model‐based analysis, including simulations, was employed to characterize the relationship between individual M100240 drug exposure and neurohormonal response and to optimize the dose selection for future clinical studies. Sixty‐two healthy subjects and 189 hypertensive patients were studied after oral once‐daily administration of 2.5, 5, 10, 25, or 50 mg M100240. Pharmacokinetic‐biomarker and blood pressure response models were fitted to the data with the computer program NONMEM. A direct inhibitory Emaxmodel adequately described the relationship between MDL100,173 concentration and ACE activity. No clear concentration or dose‐dependent NEP or blood pressure responses were evident. Given a target 90% ACE inhibition, simulation reveals that (1) 50 mg M100240 once daily produces adequate ACE inhibition 24 hours postdose in only 20% of subjects, and (2) higher and/or more frequent doses on the order of 25 mg three times daily or 50 mg twice daily are required to achieve the target ACE inhibition in at least 50% of patients over 24 hours. Insufficient blood pressure—lowering effects were observed in healthy subjects and hypertensive patients due to inadequate ACE and NEP inhibition with once‐daily oral doses of up to 50 mg of M100240. Divided doses might provide target ACE inhibition in more patients.

ABSTRACTThe goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CLdiff) and active efflux clearance (CLactive) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CLdiff, and efflux clearance is the sum of CLdiff, CLactive, and bulk flow clearance (CLbulk). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CLbulkof 0.01 ml/min, CLactivewas estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.

ABSTRACTThe present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P= 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P< 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

Objective: Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates forand inhibitors of CYP3A4. The goal of this model-based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms toaccount for them.Methods: One hundred seventy-six HIV-positive subjects receiving 1200 mg amprenavir twice daily as part of AACTG protocol 398 were included in the pharmacokinetic study. All patients also received background medications efavirenz, adefovir dipivoxil, and abacavir and, depending on the study arm, placebo or one of the following protease inhibitors: nelfinavir, indinavir, or saquinavir. A population pharmacokinetic model was fitted to a total of 565 amprenavir concentration measurements. The blood samples for concentration measurements were drawn at week 2 (12-hour pharmacokinetic study, approximately 7 samples per study; 46 patients) and at week 24 (6-hour pharmacokinetic study, approximately 5samples per study; 10 patients). In addition, samples were collected at 1 or more follow-up visits (population pharmacokinetic study, 1 to 3 occasions per patient; 150 patients).Results and Conclusion: Amprenavir intrinsic clearance was significantly reduced relative to placebo by nelfinavir (−41%) and indinavir (−54%)but not by saquinavir. The absolute magnitude of amprenavir intrinsic clearance suggests that CYP3A4 inhibition by nelfinavir and indinavir is balanced by enzymatic induction in the presence of the background drug(s), most likely efavirenz. Amprenavir intrinsic clearance apparently increases by more than 30% between weeks 2 and 24, possibly because of the time course of CYP3A4 induction.

ABSTRACTBMS 284756 penetrated well into inflamed meninges (44% ± 11%) and produced good bactericidal activity (−0.82 ± 0.22 Δlog10CFU/ml · h) in the treatment of experimental meningitis in rabbits due to a penicillin-sensitive strain. BMS 284756 monotherapy had a greater potency than the standard regimen of ceftriaxone and vancomycin (−0.49 ± 0.08 Δlog10CFU/ml · h) against a penicillin-resistant strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, BMS 284756 showed good bactericidal activity (−0.52 ± 0.12 Δlog10CFU/ml · h). The antibacterial activity of BMS 284756 was confirmed by time-killing assays over 8 h in vitro.

Limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal function deterioration.

AbstractThe carbohydrate antigen 19–9 (CA 19–9), a determinant (sialylated lacto-N-fucopentaose 119) of a circulating oligosaccharide antigen, is a frequently used tumor marker. Echinococcusspp. infects humans throughout the world and may be able to synthesize closely related molecules which could interfere with the measurement and interpretation of CA 19–9 concentration. The main objective of the present study was to determine the range of CA 19–9 levels in the sera of patients infected by E. granulosus(cystic hydatide disease; CYSHD) or E. multilocularis(alveolar hydatide disease; ALVHD).Serum samples were collected from patients (aged 10–85 years) over a period of 5 years: from 19 patients with CYSHD and from 20 patients with ALVHD. Infection was confirmed by positive Echinococcusserology and clinical evidence provided by imaging and/or histopathological findings.CA 19–9 was detectable in 13 patients with CYSHD (13.5 ± 8.5 kU/l) and 13 patients with ALVHD (30.0 ± 21 kU/l; p < 0.05). Thus ALVHD patients exhibited a significantly higher plasma level of CA 19–9 than CYSHD patients. The serum level of CA 19–9 assessed with an increased cut-off value (> 22 kU/l) was elevated in nine (45%) of 20 ALVHD patients compared to two (11%) of 19 CYSHD patients (p < 0.05).Sera from patients with Echinococcus multilocularisinfection contain substances which cross-react with CA 19–9. These substances originate either from the parasite or are synthesized by the host in response to the infection, and possibly bear the Lewis-a antigen or closely related structures which are recognized by anti-CA 19–9 antibodies. Our findings are relevant to the investigation of patients presenting with cystic lesions for which the differential diagnosis includes an infectious or neoplastic origin.

Accessory hemodialysis equipment, including dialysis cannulas, usually lack controlled and independent testing before being introduced onto the market. The aim of this study is a prospective comparison of a newly designed curved-tip dialysis cannula with a standard dialysis cannula of the same size from the same manufacturer. Fifteen chronic dialysis patients were enrolled onto a prospective 4-month crossover study. All patients had arteriovenous fistulas, except for two patients with polytetrafluoroethylene grafts. The routinely used standard cannulas were replaced by either a curved-tip 15G cannula or a new standard 15G cannula from the same manufacturer. The two cannulas were compared with respect to puncture-related pain and/or problems and bleeding complications, as well as blood-flow dynamics. Venous and arterial access pressures were recorded at blood-flow rates of 100 to 400 mL/min. Linear regression analyses of arterial and venous pressure profiles showed the same regression lines for the standard and curved-tip cannulas. Plasma haptoglobulin levels and occlusion times necessary to stop bleeding after removal of the cannulas did not differ between the two cannulas. Both patients and nurses independently reported equal puncture-related pain and/or problems for both cannulas on visual analogue scales. No correlation was found between puncture problems reported by nurses and puncture pain reported by patients. The curved-tip cannula does not offer an advantage compared with the less expensive standard cannula. Controlled testing of advertised advantages by manufacturers of accessory equipment should be a prerequisite before introduction into routine clinical treatment.

To ameliorate the clinical performance of nephrologists, improving their clinical judgment is crucial. No methodology for judgment analysis in nephrology is currently available. Therefore, we designed a trial to assess the intraphysician consistency of the judgment of typical non–end-stage renal disease (ESRD) patients by 24 board-certified nephrologists. The participants were asked to analyze cases to determine the interobserver variability with respect to diagnosis, therapy, prognosis, and strategy of follow-up. They were unaware that every patient was presented on 2 occasions separated by a period of 6 months. Of the 1,288 questionnaires that were completed, 28 cases belonged to 1 of the following 3 groups: (A) patients once with, once without renal histology, (B) patients twice without histology, and (C) patients twice with histology. Only cases of group (A) differed at the 2 occasions of assessment with respect to knowledge of histology. The results from the first and second assessment were compared and analyzed. The median (95% confidence interval) percentages of changed diagnoses were 64% (59% to 68%), 50% (44% to 62%), and 33% (26% to 47%) in groups A, B, and C, respectively, indicating large intraobserver variability. The frequency of changes in diagnoses declined with the degree of confidence in the first diagnosis in all 3 groups. The subjective desire to know the histology was without impact on the frequency of changes in diagnoses. However, a knowledge of the histology enhanced the degree of confidence in the diagnoses. Interestingly, the enormous variability in changing diagnoses from one analysis to the other was not reflected by corresponding changes in the judgment of prognosis, therapy to be prescribed, or strategy of follow-up. The individual judgment with respect to diagnosis of clinical cases is inconsistent and highly dependent on the subjective degree of confidence in the diagnosis. The practical relevant consequences traditionally derived from a diagnosis (therapy, prognosis, and strategy of follow-up) are only marginally, if at all, affected by changing the diagnosis. Thus, the utility of “diagnosis” for judgment analysis in clinical nephrology should be reconsidered.

MAILLAT D., LECOQ B., NEMETI F. and PFISTER M. (1995) Technology district and innovation: the case of the Swiss Jura Arc, Reg. Studies 29, 251-263. The Swiss Jura Arc offers an interesting illustration of the emergence and construction of a local system of production and innovation linked to the development of new technologies. The proposed approach is based on a stylized description of the processes of transformation - understood as processes of breaking-affiliation - of a conventional production system based mainly on precision engineering and watchmaking, into a production system centred on microtechnologies resulting from a combination of conventional technologies (micro-engineering) and new technologies (e.g. micro-electronics, new materials, optics). The purpose of this paper is thus to understand the transition processes that have occurred over a long period of time in the Swiss Jura Arc by showing how a technology district gradually formed from the players' ability to adapt to structural changes by taking innovative decisions which reconfigure the production process and the organization of a territory into a dynamic. In particular, this approach highlights the role of territorial environment - the milieu1 - in the processes of innovating and constructing new production options, emphasizing in particular the phenomena of dynamic complementarities and interdependencies between production agents and local institutions. This approach thus identifies a number of new proposals about the theoretical linkage between industrial dynamic, technological dynamic and territorial dynamic.MAILLAT D., LECOQ B., NEMETI F. and PFISTER M. (1995) District technologique et innovation: le cas de l'Arc jurassien suisse, Reg. Studies 29, 251-263. L'Arc jurassien suisse offre une illustration intéressante de l'emergence et de la construction d'un systeme localisé de production et d'innovation lié au développement de nouvelles technologies. La démarche proposée s'appuie sur une description stylisée des processus de transformation- entendue comme un processus de rupture-filiation - d'un systéme productif traditionnel, fondé essentiellement sur la mécanique de precision et l'horlogerie, vers un systeme de production articulé autour des activites microtechniques qui procedent d'une combinaison de technologies traditionnelles (micromécanique) et de technologies nouvelles (micro-électronique, nouveaux matériaux, optique). L'enjeu de cet article est ainsi de saisir les processus de transition qui se sont opérés sur la longue période dans l'Arc jurassien suisse, en montrant comment un district technologique s'est progressivement constitué à partir de la capacité des agents à s'adapter au changement structurel en s'engageant dans des choix innovateurs qui reconfigurent en dynamique le processus de production et l'organisation d'un territoire. Cette réflexion permet en particulier de mettre en évidence le rôle de l'environnement territorial-le milieu1-dans les processus d'innovation et de construction de nouvelles options productives, en soulignant en particulier les phénoménes de comple-mentarites et d'interdépendances dynamiques entre agents productifs et institutions locales. Cette approche permet ainsi de dégager un certain nombre de propositions nouvelles quant à l'articulation théorique entre dynamique industrielle, dynamique technologique et dynamique des territoires.MAILLAT D., LECOQ B., NEMETI F. und PFISTER M. (1995) Technologiedistrikt und Innovation: der Fall des Schweizer Jurabogens, Reg. Studies 29, 251-263. Der Schweizer Jurabogen stellt ein interessantes Beispiel des Aufkommens und Aufbaus eines örtlich begrenzten Systems von Produktion und Innovation dar, das in Verbindung mit der Entwicklung neuer Technologien aufgetreten ist. Das hier vorgeschlagene Angehen der Erforschung fußt auf einer stylisiereten Beschreibung des Transformationsvorganges - der als Vorgang des Bruchs von Bindungen verstanden wird - eines konventionellen Produk-tionssystems, das vorwiegend aus Präzisionsmaschinenbau und Uhrenbau bestand, zu einem sich auf Mikrotechnologien konzentrierenden Produktionssystem, welches sich aus einer Verbindung konventioneller Technologien (Mikromaschinen-bau) und neuer Technologien (Mikroelektonik, neue Materi-alien, Optik) ergibt. Dieser Aufsatz beabsichtigt darum, die Übergangsprozesse zu verdeutlichen, die seit langem im Schweizer Jurabogen am Werke sind, in dem er aufzeigt, wie ein technologischer Distrikt allmählich aus der Fähigkeit der Spieler entstand, sich strukturellem Wandel anzupassen, indem man innovative Entscheidungen traf, welche den Produk-tionsvorgang und die Organisation eines Gebietes zu einem dynamischen Ganzen umgestalteten. Dieses Vorgehen hebt besonders die Rolle des Umlandgebiets - des Milieus1 - bei den Vorgängen der Innovation und des Aufbaus neuer Pro-duktiosnoptionen hervor, wobei besonders die Phänomene dynamischer Komplimentaritäten und gegenseitiger Abhängigkeiten von Produktionsleitem und örtlichen Institutionen betont wird. Dieses Vorgehen identifiziert somit eine Anzahl neuer Vorschläge fur die theoretische Verknüpfung von industrieller, technologischer und territorialer Dynamik.

ABSTRACTOptimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.