Subtherapeutic Exposure Research Articles

A Clinical Study to Examine the Potential Effect of Lansoprazole on the Pharmacokinetics of Bosutinib when Administered Concomitantly to Healthy Subjects

Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect bosutinib absorption. The objectives of this study were to evaluate the effect of lansoprazole, a gastric proton pump inhibitor, on the pharmacokinetics and safety of bosutinib. This open-label, non-randomized, phase I study involved inpatients and outpatients at a single site. The study participants were healthy men or women of non-childbearing potential aged 18-50 years. Each subject received bosutinib 400 mg on Day 1, lansoprazole 60 mg on Day 14, and bosutinib 400 mg co-administered with lansoprazole 60 mg on Day 15 under fasting conditions. The main outcome measure was the effect of multiple doses of lansoprazole on the pharmacokinetic profile of a single oral dose of bosutinib. A total of 24 healthy male subjects were enrolled. Co-administration with lansoprazole decreased the mean maximum plasma concentration (C(max)) of bosutinib from 70.2 to 42.9 ng/mL, and the total area under the plasma concentration-time curve (AUC) from 1,940 to 1,470 ng·h/mL. Log-transformed bosutinib pharmacokinetic parameters indicated significant between-treatment differences; the least squares geometric mean ratio for C(max) was 54 % (95 % CI 42-70) and for AUC was 74 % (95 % CI 60-90). Mean apparent total body clearance from plasma after oral administration increased from 237 to 330 L/h, and the median time to reach Cmax increased from 5 to 6 h, although this change may be related to decreased bosutinib absorption when combined with lansoprazole. When co-administered with lansoprazole, bosutinib maintained an acceptable safety profile, which was primarily characterized by diarrhea (33 %), headache (21 %), and nausea (13 %). One subject experienced serious adverse events of diverticulitis, gastritis, and duodenitis after co-administration; however, no participant withdrew because of toxicity. This study demonstrated that bosutinib absorption may be reduced when co-administered with lansoprazole or other proton pump inhibitors. Caution should be used with such drug combinations, as subtherapeutic exposure of bosutinib may limit its clinical antitumor activity; short-acting antacids are recommended instead.

The influence of gastrointestinal resection on sunitinib exposure in GIST patients.

10547 Background: GIST patients often have an altered anatomy of the GI tract due to either primary resection of the tumor or palliative surgery. It is unknown whether such GI resections affect the exposure to sunitinib and its active metabolite SU12662. Previous studies showed that the exposure to imatinib and nilotinib was decreased in GIST patients with prior major gastrectomy. Therefore, we postulated that GI resections might similarly affect sunitinib exposure. Methods: A retrospective analysis was performed to assess the effect of GI resections on sunitinib exposure. Pharmacokinetic data from 305 GIST patients included in 4 phase I-II trials were analyzed. Patients were subdivided into 6 groups according to prior GI surgery: 1)Major gastrectomy: 2)Partial gastrectomy: 3)Small bowel resection: 4)Combination of gastrectomy and small bowel resection: 5)Colon resection and 6)Controls with no prior GI surgery. Patients with uncertain GI resections were excluded. Dose normalized exposure (AUC0-24hr) of sunitinib and SU12662 was estimated with a population PK approach using NONMEM. Analysis of covariance was performed to test for significant differences in AUC between each of the subgroups and controls. Results: The geometric mean of total exposure to sunitinib and SU12662 was decreased by 21% and 28% in subgroup 4, (n=8; sunitinib: 931 ng*hr/mL (95%CI;676-1283) and SU12662: 354 ng*hr/mL (95%CI;174-720)) compared to controls (n=63; sunitinib: 1177 ng*hr/mL (95%CI;1097-1263) and SU12662: 491 ng*hr/mL (95%CI;435-555)), with the differences being significant (p<0.05) on the log scale. However, no significant differences in total exposures were observed between each of the other subgroups and control. Conclusions: In patients with a combined gastrectomy and small bowel resection, sunitinib and SU12662 exposure is significantly decreased as compared to subjects with no prior GI surgery. Contrary to previous results for imatinib, gastrectomy alone does not appear to influence sunitinib exposure. This should be taken into consideration for the treatment of GIST patients who had a gastrectomy. In theory, such patients might have better outcomes if treated with sunitinib, given the risk of subtherapeutic exposure to imatininb.

Insufficient serum caspofungin levels in a paediatric patient on ECMO

Caspofungin, aechinocandin, is a relatively new lipophilic antifungal drug. Little is known concerning the pharmacokinetics of caspofungin in children. Extracorporeal membrane oxygenation (ECMO) allows prolonged cardiopulmonary support in patients with life-threatening respiratory or cardiac failure. Pharmacokinetics may be altered by ECMO. We describe the case of a paediatric patient on ECMO with severe pneumonia and sepsis, who had subtherapeutic exposure of caspofungin despite normal to high dosages of caspofungin. Therapeutic drug monitoring is warranted.

Decreased meropenem levels in Intensive Care Unit patients with augmented renal clearance: benefit of therapeutic drug monitoring

One of the first-line drugs for empirical antibiotic therapy in patients with hospital-acquired infections is meropenem. An often neglected problem in sepsis is that patients with a normal serum creatinine concentration (SCr) might display augmented renal clearance (ARC). Here we describe two cases of sepsis with subtherapeutic exposures with standard meropenem dosing in whom therapy could be optimised by therapeutic drug monitoring (TDM). A 37-year-old man with acute lymphatic leukaemia and sepsis had a normal SCr at the beginning of his Intensive Care Unit (ICU) stay but showed decreased SCr of between 30μmol/L and 40μmol/L during his stay. He failed to achieve effective plasma concentrations with the meropenem standard dose of 3g/day. Estimated glomerular filtration rate revealed values between 120mL/min and 160mL/min. He required a high meropenem daily dosage of 12g that was far above the approved maximum dose. A 66-year-old patient undergoing surgery of a pulmonary aspergilloma presented SCr persistently <50μmol/L, indicating ARC between 120mL/min and 150mL/min. This patient required 8g of meropenem to achieve effective plasma concentrations. TDM may represent an invaluable approach to optimising drug exposure of β-lactam antibiotics in patients with ARC in the ICU. Further trials are clearly needed to become better informed about empirical dosing regimens usable in the ICU setting with regard to the relevance of ARC. In the meantime, daily measurement of creatinine clearance as well as TDM can be used to identify patients who manifest ARC, thereby allowing drug therapy to achieve the therapeutic range.

The Antibiotic Resistance Arrow of Time: Efflux Pump Induction Is a General First Step in the Evolution of Mycobacterial Drug Resistance

We hypothesize that low-level efflux pump expression is the first step in the development of high-level drug resistance in mycobacteria. We performed 28-day azithromycin dose-effect and dose-scheduling studies in our hollow-fiber model of disseminated Mycobacterium avium-M. intracellulare complex. Both microbial kill and resistance emergence were most closely linked to the within-macrophage area under the concentration-time curve (AUC)/MIC ratio. Quantitative PCR revealed that subtherapeutic azithromycin exposures over 3 days led to a 56-fold increase in expression of MAV_3306, which encodes a putative ABC transporter, and MAV_1406, which encodes a putative major facilitator superfamily pump, in M. avium. By day 7, a subpopulation of M. avium with low-level resistance was encountered and exhibited the classic inverted U curve versus AUC/MIC ratios. The resistance was abolished by an efflux pump inhibitor. While the maximal microbial kill started to decrease after day 7, a population with high-level azithromycin resistance appeared at day 28. This resistance could not be reversed by efflux pump inhibitors. Orthologs of pumps encoded by MAV_3306 and MAV_1406 were identified in Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium abscessus, and Mycobacterium ulcerans. All had highly conserved protein secondary structures. We propose that induction of several efflux pumps is the first step in a general pathway to drug resistance that eventually leads to high-level chromosomal-mutation-related resistance in mycobacteria as ordered events in an "antibiotic resistance arrow of time."

UGT1A4*3 Encodes Significantly Increased Glucuronidation of Olanzapine in Patients on Maintenance Treatment and in Recombinant Systems

Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.

COMMENTARY

COMMENTARY

Improving vancomycin prescription in critical illness through a drug use evaluation process: a weight-based dosing intervention study

Vancomycin is currently recommended as first-line therapy for many meticillin-resistant Staphylococcus aureus (MRSA) infections. Recent guidelines have advocated loading doses (25–30 mg/kg) in critically ill patients in order to achieve therapeutic concentrations rapidly. However, weight-based loading doses are still not widely practised. A drug use evaluation was performed to improve the appropriateness of vancomycin initial doses in a population of critically ill adults. An educational intervention incorporating a vancomycin dosing protocol was carried out. Data were collected pre and post intervention. Vancomycin exposure [area under the concentration–time curve (AUC)] in the first 24 h was determined using serum concentrations and the Bayesian software TCIWorks. Initial vancomycin doses and exposures were compared between the pre- and post-intervention groups using χ 2 and Mann–Whitney tests. A total of 111 vancomycin courses were analysed in the pre-intervention ( n = 80) and post-intervention ( n = 31) groups. Patients in the post-intervention group had significantly higher median weight-based initial doses (20.0 mg/kg vs. 12.5 mg/kg; P < 0.001) compared with the pre-intervention group. This corresponded to significantly higher median vancomycin exposures (366.0 mg h/L vs. 262.5 mg h/L; P < 0.01) in the post-intervention group. Despite higher weight-based initial doses, only 32.3% of patients in the post-intervention group had achieved optimal vancomycin exposures (AUC/minimum inhibitory concentration ratio ≥400) in the first 24 h of therapy. A vancomycin dosing protocol improved the initial dosing of vancomycin and the proportion of patients who rapidly achieved optimal vancomycin exposures. However, subtherapeutic exposures were still prevalent and may warrant more vigilant promotion of the dosing protocol to ensure that recommended vancomycin doses are used in this population.

Therapeutic Monitoring and Variability of Atazanavir in HIV-Infected Patients, With and Without HCV Coinfection, Receiving Boosted or Unboosted Regimens

Adequate plasma trough concentrations (Ctrough) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection. We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 μg/mL, based on the proposed therapeutic range (0.15-0.85 μg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV-, HIV+/HCV+, and HIV+/HCV+ with cirrhosis. In the whole study population, we observed a large variability and found suboptimal Ctrough levels (<0.15 μg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) μg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median Ctrough of 0.70 (0.43-1.0) μg/mL, with no statistical difference when compared with HIV+/HCV- infected patients. For the 400ATV OD (n=90) dosage regimen, the total median ATV Ctrough was 0.40 (0.23-1.0) μg/mL. In this group, we found a statistically significant difference between HIV+/HCV- and HIV+/HCV+-infected patients: median Ctrough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) μg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the Ctrough median value was 0.42 (0.13-0.75) μg/mL, and there was a significant difference when compared with HIV patients without coinfection. Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIV-infected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.

Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals.

BackgroundNevirapine is metabolized by CYP2B6 and polymorphisms within the CYP2B6 gene partly explain inter-patient variability in pharmacokinetics. The aim of this study was to model the complex relationship between nevirapine exposure, weight and genetics (based on combined analysis of CYP2B6 516G > T and 983T > C single nucleotide polymorphisms).MethodsNon-linear mixed-effects modelling was used to estimate pharmacokinetic parameters from 275 patients. Simulations of the nevirapine concentration profile were performed with dosing regimens of 200 mg twice daily and 400 mg once daily for individuals with body weights of 50, 70 and 90 kg in combination with CYP2B6 genetic variation.ResultsA one-compartment model with first-order absorption best described the data. Population clearance was 3.5 L/h with inter-patient variability of 24.6%. 516T homozygosity and 983C heterozygosity were associated with 37% and 40% lower clearance, respectively. Body weight was the only significant demographic factor influencing clearance, which increased by 5% for every 10 kg increase. For individuals with higher body weight, once-daily nevirapine was associated with a greater risk of sub-therapeutic drug exposure than a twice-daily regimen. This risk was offset in individuals who were 516T homozygous or 983C heterozygous in which drug exposure was optimal for > 95% of patients with body weight of ≤70 kg.ConclusionsThe data suggest that a 400 mg once-daily dose could be implemented in accordance with CYP2B6 polymorphism and body weight. However, the use of nevirapine once daily (immediate release; off-label) in the absence of therapeutic drug monitoring is not recommended due to the risk of inadequate exposure to nevirapine in a high proportion of patients. There are different considerations for the extended-release formulation (nevirapine XR) that demonstrate minimal peak-to-trough fluctuations in plasma nevirapine levels.

Posaconazole cerebrospinal concentrations in an HIV-infected patient with brain mucormycosis

of daptomycin by Etest (AB Biodisk) was 0.125 mg/L. Informed consent was obtained from the patient’s next of kin and therapy with daptomycin was started at a daily dose of 8 mg/kg; the other antibiotics were stopped. The high dose of daptomycin was chosen because of the elevated volume of distribution (which is typical of septic patients, together with lower plasma albumin concentrations) and because polysulphone daptomycin clearance is higher than for other types of ultrafiltration. It was not possible to determine plasma concentrations of daptomycin, and we therefore decided to monitor plasma concentrations of creatinine phosphokinase (CPK), aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase to exclude myopathy, a wellrecognized adverse effect of daptomycin. Since CPK can be eliminated by CVVH, we also measured the ultrafiltrate concentrations of CPK. The plasma concentration of CPK always remained ≤200 IU/L (normal: 50–397 IU/L) and the ultrafiltered CPK concentration never exceeded 86 IU/L. The patient’s condition improved and therapy was discontinued after 14 days. Dosing of antibiotics for patients in intensive care can be challenging, particularly when they undergo renal replacement therapy. Ideally, plasma concentrations should be checked regularly, but this may be impractical in real time. Data from in vitro models of CRRT suggest that a substantial amount of daptomycin can be removed. Since we could not monitor antibiotic concentrations in order to avoid subtherapeutic exposure, we decided to use a higher daily dose (8 mg/kg) and no adverse effects were demonstrated. Despite the limitations of this report we suggest that higher doses can be given safely in CRRT, but patients should be closely monitored for evidence of myopathy. Further studies, with plasma monitoring, are required to refine dosage regimens for CRRT.

Evaluation of drug–drug interactions with fesoterodine

To assess drug-drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C(max); from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C(max) (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives.

Genital Tract, Cord Blood, and Amniotic Fluid Exposures of Seven Antiretroviral Drugs during and after Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women

The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.

Daptomycin elimination by CVVH in vitro: evaluation of factors influencing sieving and membrane adsorption

Knowledge on the elimination of antibiotics by extracorporeal hemofiltration is a prerequisite for appropriate antimicrobial dosing in patients with renal failure. The present study set out to determine the clearance of the novel lipopetide antibiotic daptomycin from human whole blood by continuous venovenous hemofiltration (CVVH) in vitro. In addition, factors influencing daptomycin sieving and membrane adsorption were investigated. A recirculation model using different solvent media was established and daptomycin was added to the simulated blood circuit at varying concentrations. The concentration of daptomycin over time in the modelled blood compartment and the ultrafiltrate was measured by high performance liquid chromatography (HPLC). Mean Sieving coefficients (SCs) of daptomycin over time were calculated to 0.98 +/- 0.05, 0.33 +/- 0.02 and 0.40 +/- 0.03 at a baseline concentration of 60 microg/ml in Ringer lactate, Ringer lactate containing human albumin and in human whole blood, respectively. SCs of daptomycin in protein-containing media were higher than the free fraction in plasma of approximately 10%. Neither concentration of daptomycin nor addition of a second antibiotic showed significant impact on the SC. Adsorption of daptomycin to synthetic surfaces proved moderate and saturable, resulting in loss of around 20% of the amount initially added to the artificial blood circuit. In our in vitro setting the calculated clearance of daptomycin from whole blood exceeded the physiological clearance described for individuals with normal renal function. Investigation of clearance by CVVH in vivo seems necessary. Until sufficient clinical data are available for patients undergoing CVVH, monitoring of daptomycin concentrations in this population might be recommended in order to avoid sub-therapeutic exposure to daptomycin.

All Dex’ed Out With Nowhere to Go?

All Dex’ed Out With Nowhere to Go?

Industrial Food Animal Production, Antimicrobial Resistance, and Human Health

Antimicrobial resistance is a major public health crisis, eroding the discovery of antimicrobials and their application to clinical medicine. There is a general lack of knowledge of the importance of agricultural antimicrobial use as a factor in antimicrobial resistance even among experts in medicine and public health. This review focuses on agricultural antimicrobial drug use as a major driver of antimicrobial resistance worldwide for four reasons: It is the largest use of antimicrobials worldwide; much of the use of antimicrobials in agriculture results in subtherapeutic exposures of bacteria; drugs of every important clinical class are utilized in agriculture; and human populations are exposed to antimicrobial-resistant pathogens via consumption of animal products as well as through widespread release into the environment.

Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers

The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios. The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios. This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects. The observed differences in omeprazole AUC(infinity) suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure. AIMS To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers. In a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography. The mean omeprazole AUC(infinity) of 1973 h nmol l(-1) in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l(-1), P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC(infinity) of 1083 h nmol l(-1), 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l(-1), P = 0.03). A pronounced correlation (r(2) = 0.95, P < 0.0001) was seen in the intraindividual omeprazole AUC(infinity) and omeprazole sulphone AUC(infinity) values. The pharmacokinetics of omeprazole and omeprazole sulphone differ significantly between homozygous CYP2C19*17 and CYP2C19*1 subjects. For clinically important drugs that are metabolized predominantly by CYP2C19, the CYP2C19*17 allele might be associated with subtherapeutic drug exposure.

Antiretroviral Treatment Strategies and Immune Reconstitution in Treatment-naive HIV-Infected Patients with Advanced Disease

Treatment-naïve advanced HIV-infected patients have a lower life expectancy than those treated early with highly active antiretroviral therapy (HAART). Early treatment allows greater immunological recovery, a reduction of AIDS progression, a reduced risk of related illnesses, and lower mortality compared with HAART initiation in advanced disease. Given the numbers with advanced disease worldwide and the high cost of care, strategies encouraging early detection may be life saving and cost effective. Factors associated with increased clinical progression include higher baseline HIV viral load and older age, emphasizing the need for early viral load suppression. HAART initiation faces many challenges; interactions between antiretroviral agents and drugs used to treat life-threatening opportunistic infections may cause subtherapeutic antiretroviral exposure and the development of resistance or supratherapeutic levels resulting in adverse effects. Immune reconstitution inflammatory syndrome can be another cause of suboptimal outcomes. The management of patients with advanced HIV infection should include rapid short-term immune reconstitution to limit the risk of disease progression plus aggressive antiviral treatment to achieve rapid virological suppression. Clear evidence on the optimal regimen and agents to use to target advanced HIV disease is lacking. Therefore, antiretroviral treatment for these patients has to be carefully tailored to the individual according to many variables.

Design and development of a prototype endocavitary probe for high‐intensity focused ultrasound delivery with integrated magnetic resonance imaging

To integrate a high intensity focused ultrasound (HIFU) transducer with an MR receiver coil for endocavitary MR-guided thermal ablation of localized pelvic lesions. A hollow semicylindrical probe (diameter 3.2 cm) with a rectangular upper surface (7.2 cm x 3.2 cm) was designed to house a HIFU transducer and enable acoustic contact with an intraluminal wall. The probe was distally rounded to ease endocavitary insertion and was proximally tapered to a 1.5-cm diameter cylindrical handle through which the irrigation tubes (for transducer cooling) and electrical connections were passed. MR compatibility of piezoceramic and piezocomposite transducers was assessed using gradient-echo (GRE) sequences. The radiofrequency (RF) tuning of identical 6.5 cm x 2.5 cm rectangular receiver coils on the upper surface of the probe was adjusted to compensate for the presence of the conductive components of the HIFU transducers. A T1-weighted (T1-W) sliding window dual-echo GRE sequence monitored phase changes in the focal zone of each transducer. High-intensity (2400 W/cm(-2)), short duration (<1.5 seconds) exposures produced subtherapeutic temperature rises. For T1-W images, signal-to-noise ratio (SNR) improved by 40% as a result of quartering the conductive surface of the piezoceramic transducer. A piezocomposite transducer showed a further 28% improvement. SNRs for an endocavitary coil in the focal plane of the HIFU trans-ducer (4 cm from its face) were three times greater than from a phased body array coil. Local shimming improved uniformity of phase images. Phase changes were detected at subtherapeutic exposures. We combined a HIFU transducer with an MR receiver coil in an endocavitary probe. SNRs were improved by quartering the conductive surface of the piezoceramic. Further improvement was achieved with a piezocomposite transducer. A phase change was seen on MR images during both subtherapeutic and therapeutic HIFU exposures.

Evaluation of Accessory Gene Regulator ( agr ) Group and Function in the Proclivity towards Vancomycin Intermediate Resistance in Staphylococcus aureus

Simulated therapeutic vancomycin exposures were evaluated against agr wild-type and knockout Staphylococcus aureus groups I, II, III, and IV using an in vitro pharmacodynamic model. All agr groups developed intermediate resistance to vancomycin after subtherapeutic exposure. The free unbound fraction of the area under the concentration-time curve (fAUC/MIC) required to suppress resistance was fourfold higher (P < 0.001) in agr dysfunctional strains (112 to 169) than that in parent wild-type strains (28).