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Stephen Toovey,
Eric P Prinssen, Craig R Rayner,
Bharat T Thakrar,
Regina Dutkowski,
Annette Koerner,
Tom Chu,
Alexandra Sirzen-Zelenskaya,
Markus Britschgi,
Sudhir Bansod,
Barbara Donner
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ABSTRACT: A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.Supplementary material is available on SpringerLink.com.
Advances in Therapy 10/2012; 29(10):826-48. · 2.11 Impact Factor
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Agnès Poirier,
Sara Belli,
Christoph Funk,
Michael B Otteneder,
Renée Portmann,
Katja Heinig,
Eric Prinssen,
Stanley E Lazic, Craig R Rayner,
Gerhard Hoffmann,
Thomas Singer,
David E Smith,
Franz Schuler
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ABSTRACT: It was reported that oseltamivir (Tamiflu) absorption was mediated by human peptide transporter (hPEPT) 1. Understanding the exact mechanism(s) of absorption is important in the context of drug-drug and diet-drug interactions. Hence, we investigated the mechanism governing the intestinal absorption of oseltamivir and its active metabolite (oseltamivir carboxylate) in wild-type [Chinese hamster ovary (CHO)-K1] and hPEPT1-transfected cells (CHO-PEPT1), in pharmacokinetic studies in juvenile and adult rats, and in healthy volunteers. In vitro cell culture studies showed that the intracellular accumulation of oseltamivir and its carboxylate into CHO-PEPT1 and CHO-K1 was always similar under a variety of experimental conditions, demonstrating that these compounds are not substrates of hPEPT1. Furthermore, neither oseltamivir nor its active metabolite was capable of inhibiting Gly-Sar uptake in CHO-PEPT1 cells. In vivo pharmacokinetic studies in juvenile and adult rats showed that the disposition of oseltamivir and oseltamivir carboxylate, after oral administration of oseltamivir, was sensitive to the feed status but insensitive to the presence of milk and Gly-Sar. Moreover, oseltamivir and oseltamivir carboxylate exhibited significantly higher exposure in rats under fasted conditions than under fed conditions. In humans, oral dosing after a high-fat meal resulted in a statistically significant but moderate lower exposure than after an overnight fasting. This change has no clinical implications. Taken together, the results do not implicate either rat Pept1 or hPEPT1 in the oral absorption of oseltamivir.
Drug metabolism and disposition: the biological fate of chemicals 05/2012; 40(8):1556-65. · 3.74 Impact Factor
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ABSTRACT: Oseltamivir (Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an orally administered antiviral for the treatment and prevention of influenza A and B infections that is registered in more than 100 countries worldwide. More than 83 million patients have been exposed to the product since its introduction. Oseltamivir is recommended by the World Health Organization (WHO) for use in the clinical management of pandemic and seasonal influenza of varying severity, and as the primary antiviral agent for treatment of avian H5N1 influenza infection in humans. This article is a nonsystematic review of the experience gained from the first 10 years of using oseltamivir for influenza infections since its launch in early 2000, emphasizing recent advances in our understanding of the product and its clinical utility in five main areas. The article reviews the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate, including information on special populations such as children and elderly adults, and the co-administration of oseltamivir with other agents. This is followed by a summary of data on the effectiveness of oseltamivir treatment and prophylaxis in patients with all types of influenza, including pandemic (H1N1) 2009 and avian H5N1 influenza. The implications of changes in susceptibility of circulating influenza viruses to oseltamivir and other antiviral agents are also described, as is the emergence of antiviral resistance during and after the 2009 pandemic. The fourth main section deals with the safety profile of oseltamivir in standard and special patient populations, and reviews spontaneously reported adverse event data from the pandemic and pre-pandemic periods and the topical issue of neuropsychiatric adverse events. Finally, the article considers the pharmacoeconomics of oseltamivir in comparison with vaccination and usual care regimens, and as a component of pandemic influenza mitigation strategies.
Advances in Therapy 11/2011; 28(11):927-59. · 2.11 Impact Factor
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Naohisa Uchimura,
Hiroo Kuwahara,
Yuji Kumagai,
Kazuo Mishima,
Yuichi Inoue, Craig R Rayner,
Stephen Toovey,
Brian E Davies,
Yoshio Hosaka,
Masaichi Abe,
Eric P Prinssen
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ABSTRACT: Influenza-associated neuropsychiatric symptoms include parasomnias such as sleepwalking which is a common sleep disturbance in childhood. Oseltamivir is a widely used antiviral drug for influenza. Recently, sleepwalking-like events have been reported in patients with influenza receiving oseltamivir. We investigated whether oseltamivir itself has effects on sleep. In this crossover study, healthy Japanese male volunteers were randomized into two treatment groups, each of which comprised two double-blind 4-day treatment periods. In the first period, group A received 75 mg oseltamivir (evening dose) on day 3, followed by 75 mg b.i.d. on day 4, and placebo in the second period. Group B received the same treatments, but in reverse order. Polysomnographic assessments were performed on all four nights of each treatment period. Pharmacokinetics were assessed during a 2-day open-label phase beginning on day 12. Thirty-one volunteers aged 20-24 years were enrolled. No volunteer had electroencephalographic abnormalities, and no abnormal behaviour was observed. Sleep parameters measured over the whole night and during early- and late sleep periods (first and last thirds of the night) were very similar for oseltamivir and placebo, although the amount of stage 2 sleep in the middle sleep period was slightly greater with oseltamivir. Pharmacokinetics for oseltamivir phosphate in groups A and B were very similar, but for oseltamivir carboxylate, AUC and C(max) values were higher in group B, probably because this group received oseltamivir on the evening of day 11. Oseltamivir was well tolerated. Oseltamivir did not produce clinically relevant changes on nocturnal polysomnographic variables in young Japanese men.
Basic & Clinical Pharmacology & Toxicology 05/2011; 109(4):309-14. · 2.18 Impact Factor
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ABSTRACT: Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.
Antimicrobial Agents and Chemotherapy 12/2009; 54(3):1117-24. · 4.84 Impact Factor
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ABSTRACT: Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
Antimicrobial Agents and Chemotherapy 09/2009; 53(11):4753-61. · 4.84 Impact Factor
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ABSTRACT: Colistin methanesulfonate (CMS) has the potential to hydrolyze in aqueous solution to liberate colistin, its microbiologically active and more toxic parent compound. While conversion of CMS to colistin in vivo is important for bactericidal activity, liberation of colistin during storage and/or use of pharmaceutical formulations may potentiate the toxicity of CMS. To date, there has been no information available regarding the stability of CMS in pharmaceutical preparations. Two commercial CMS formulations were investigated for stability with respect to colistin content, which was measured by a specific high-performance liquid chromatography method. Coly-Mycin M Parenteral (colistimethate lyophilized powder) was stable (<0.1% of CMS present as colistin) for at least 20 weeks at 4 degrees C and 25 degrees C at 60% relative humidity. When Coly-Mycin M was reconstituted with 2 ml of water to a CMS concentration of 200 mg/ml for injection, Coly-Mycin M was stable (<0.1% colistin formed) for at least 7 days at both 4 degrees C and 25 degrees C. When further diluted to 4 mg/ml in a glucose (5%) or saline (0.9%) infusion solution as directed, CMS hydrolyzed faster at 25 degrees C (<4% colistin formed after 48 h) than at 4 degrees C (0.3% colistin formed). The second formulation, CMS Solution for Inhalation (77.5 mg/ml), was stable at 4 degrees C and 25 degrees C for at least 12 months, as determined based on colistin content (<0.1%). This study demonstrated the concentration- and temperature-dependent hydrolysis of CMS. The information provided by this study has important implications for the formulation and clinical use of CMS products.
Antimicrobial Agents and Chemotherapy 08/2008; 52(9):3047-51. · 4.84 Impact Factor
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ABSTRACT: Oseltamivir is a potent, selective, oral neuraminidase inhibitor for the treatment and prophylaxis of influenza. Plasma concentrations of the active metabolite, oseltamivir carboxylate, are increased in the presence of probenecid, suggesting that the combination could allow for the use of reduced doses of oseltamivir. To investigate this proposal, we developed a population pharmacokinetic model and simulated the pharmacokinetics of candidate combination regimens of oral oseltamivir (45 mg and 30 mg twice a day) plus oral probenecid (500 mg/6 hourly). Probenecid plus oseltamivir 45 mg achieved all the pharmacokinetic parameters expected of oseltamivir alone, but combination with oseltamivir 30 mg and dose interval extension approaches did not. An oseltamivir-probenecid combination may compromise tolerability and enhance the potential for drug interactions. In addition, increased dosing requirements may affect compliance and attainment of optimal oseltamivir exposure, potentially facilitating the emergence of viral strains with reduced susceptibility to oseltamivir. These factors, set alongside increased capacity for oseltamivir production, should be carefully considered before an oseltamivir-probenecid combination is used.
The Journal of Clinical Pharmacology 08/2008; 48(8):935-47. · 2.91 Impact Factor
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ABSTRACT: We have shown previously using the dually perfused isolated human placenta model that the maternal to foetal transfer of the antiviral protease inhibitor drug indinavir is substantially lower than the transfer in the opposite direction. This finding is not consistent with passive diffusion and indicates that a carrier-mediated mechanism is involved in retarding the movement in the maternal to foetal direction. The efflux transporter P-gp located in the apical membrane domain of the placental trophoblast cells has been implicated as the likely cause of the differential bi-directional transport.
The present study also utilizes the human perfused human isolated placenta to investigate the possible inhibitory effects of the P-gp inhibitor PSC833 and the P-gp substrate/inhibitor ritonavir on the maternal to foetal transfer clearance of indinavir. The studies, which were conducted such that each placenta served as its own control, demonstrated a statistically significant increase in the maternal to foetal transfer of indinavir in the presence of PSC833 but not in the presence of ritonavir, a protease inhibitor that is often used in combination with other protease inhibitors in dual therapy. The lack of effect of ritonavir is most likely related to the relatively low inhibitory activity at the clinically relevant concentration used in this study.
To investigate the effect of P-gp inhibition on the maternal to foetal transfer of indinavir.
Term human placentae (n = 12) were from non-HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P-gp inhibitors PSC833 (n = 7) or ritonavir (n = 5), in the perfused human placenta. Antipyrine and [(3)H]-vinblastine were included as markers of passive diffusion and P-gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0 min; PSC833 or ritonavir was added at 25 min. Steady-state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index).
Indinavir clearance index increased between the control (0.25 +/- 0.03) and PSC833 phases (0.37 +/- 0.14) (95% CI of the difference -0.23, -0.002). Vinblastine clearance index increased from (0.25 +/- 0.08) to (0.34 +/- 0.06) in the control and PSC833 phases, respectively (95% CI of difference -0.14, -0.05). Indinavir clearance index was unchanged between control (0.34 +/- 0.14) and ritonavir phases (0.39 +/- 0.13) (95% CI of the difference -0.19, 0.08). Vinblastine clearance index increased from (0.24 +/- 0.12) to (0.32 +/- 0.12) in the control and ritonavir phases, respectively (95% CI of the difference -0.15, -0.009).
Maternal to foetal transfer clearance of indinavir and vinblastine increased following P-gp inhibition. The potential role for co-administration of P-gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.
British Journal of Clinical Pharmacology 06/2008; 65(5):667-73. · 2.96 Impact Factor
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ABSTRACT: The relative nephro- and neurotoxicity of colistin methanesulfonate (CMS) was investigated with rats during 7 days of intravenous administration in regimens mimicking twice- and once-daily dosing of a clinically relevant dose for humans. Histological examination revealed more-severe renal lesions with the regimen corresponding to once-daily dosing, indicating that the potential for renal toxicity may be greater with extended-interval dosing.
Antimicrobial Agents and Chemotherapy 04/2008; 52(3):1159-61. · 4.84 Impact Factor
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Journal of Pharmacology and Experimental Therapeutics 08/2007; 322(1):422-3; author reply 424-5. · 3.83 Impact Factor
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ABSTRACT: The pharmacokinetics of oseltamivir and oseltamivir carboxylate in healthy Japanese (n = 14) and Caucasian (n = 14) males were compared. Subjects in each ethnic group were randomized to twice-daily oral oseltamivir 75 mg, 150 mg, or placebo for 13 doses. Oseltamivir was well tolerated across doses and ethnic groups. Oseltamivir was rapidly absorbed and hydrolyzed to oseltamivir carboxylate in all subjects. The mean plasma concentration-time profiles for oseltamivir and oseltamivir carboxylate were similar in Japanese and Caucasian subjects. At steady state, there was no evidence of any ethnic difference in the individual AUC(0-12) values for oseltamivir or oseltamivir carboxylate. Despite a significant difference in group mean body weight (approximately 20 kg) between the Japanese and Caucasian subjects, there was no evidence that dose-adjusted AUC(0-12) and C(max) for oseltamivir carboxylate were affected by body weight or ethnicity. Day 7 trough concentrations (C(min)) for oseltamivir carboxylate markedly exceeded the IC(50) (50% inhibitory concentration) against influenza A and B isolates. In conclusion, the results of this study support the use of the same dose regimens of oseltamivir in both Caucasian and Japanese subjects because of similarity in pharmacokinetics.
The Journal of Clinical Pharmacology 07/2007; 47(6):689-96. · 2.91 Impact Factor
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ABSTRACT: Emerging resistance threatens the usefulness of linezolid for the treatment of severe infections caused by multidrug-resistant gram-positive bacteria. Optimal pharmacokinetic (PK)/pharmacodynamic (PD) indices have been described for the antimicrobial efficacy of linezolid (area under the concentration-time curve over 24 h at steady state divided by the MIC, >100; the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state PK conditions, >85). The aim of this study was to investigate the influence of these PK/PD indices on the development of resistance to linezolid by using an in vitro PK/PD model. Four dosage regimens were simulated over 72 h (two intermittent bolus regimens of 600 mg every 12 h [q12h] and 120 mg q12h and two continuous-infusion regimens of 120 mg/24 h and 30 mg/24 h) against four reference strains: methicillin-resistant Staphylococcus aureus (MRSA), heteroresistant vancomycin-intermediate S. aureus (hVISA), vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant Enterococcus faecium (VRE). Linezolid concentrations were measured by high-performance liquid chromatography. Changes in susceptibility were characterized by pre- and posttreatment MIC measurements and population analysis profiles (PAPs). The linezolid concentrations that were achieved closely matched those that were targeted. The simulation with 600 mg q12h provided a >3-log10 reduction in the number of CFU/ml for all four strains, as did the 120-mg-q12h regimen for hVISA and VISA and the 30-mg/24-h continuous infusion for VRE and VISA. After 72 h of exposure to the 120-mg/24-h continuous-infusion simulation, the area under the PAP curve for all strains increased substantially (40 to 178%); increases in the MICs for the MRSA and hVISA strains were observed. The results demonstrate that PK/PD considerations are important in optimizing both antibacterial activity and the development of resistance to linezolid. The potential for resistance development appears to be higher when a constant concentration is maintained in the vicinity of the MIC of the bacteria.
Antimicrobial Agents and Chemotherapy 05/2007; 51(4):1287-92. · 4.84 Impact Factor
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ABSTRACT: To determine whether lower umbilical cord than maternal binding of indinavir and saquinavir contributed to the low cord : maternal (C : M) total concentration ratios reported previously.
Indinavir and saquinavir unbound fraction (fu) was determined using equilibrium dialysis. Buffer solutions of human serum albumin (HSA) (20.0, 30.0, 40.0 g l(-1)) and alpha(1)-acid glycoprotein (AAG) (0.20, 0.60, 2.00 g l(-1)) were spiked with indinavir (1.00 and 8.00 mg l(-1)) or saquinavir (0.15 and 1.50 mg l(-1)). Matched maternal and umbilical cord plasma was spiked with 1.00 mg l(-1) indinavir (n = 12) or 0.15 mg l(-1) saquinavir (n = 20). Spiked protein/plasma solutions were dialyzed against isotonic phosphate buffer, at 37 degrees C. At equilibrium, indinavir and saquinavir concentrations were quantified, and the f(u) determined.
Indinavir and saquinavir demonstrated protein concentration-dependent binding in buffer solutions of HSA and AAG. Indinavir f(u) was significantly higher in umbilical cord (0.53 +/- 0.12) compared with maternal (0.36 +/- 0.11) plasma (95% CI of the difference -0.26, -0.097). Similarly, saquinavir fu was different between umbilical cord (0.0090 +/- 0.0046) and maternal plasma (0.0066 +/- 0.0039) (95% CI of the difference -0.0032, -0.0016). The transplacental AAG concentration gradient contributed significantly to the binding differential of both drugs.
The differential plasma binding of both drugs, which was largely the result of the transplacental AAG concentration gradient, would contribute to the low C : M total plasma concentration ratios observed previously. Unbound concentrations of indinavir and saquinavir are likely to be substantially lower in umbilical cord than maternal plasma.
British Journal of Clinical Pharmacology 04/2007; 63(3):315-21. · 2.96 Impact Factor
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ABSTRACT: Pharmacokinetic studies of oseltamivir in very elderly patients (> or = 80 y) have not previously been performed.
To compare the pharmacokinetics of oseltamivir and the active carboxylate metabolite in healthy young and very elderly Japanese subjects.
Young (20-35 y, fasting, n = 7) and very elderly subjects (> or = 80 y, fed, n = 5) were enrolled in single-center studies and received a single oral dose of oseltamivir 75 mg. Plasma and urine samples were collected (24 h) for pharmacokinetic analysis, and safety was assessed.
The time to maximum plasma concentration (tmax) for oseltamivir was delayed in the very elderly compared with the young subjects (2.30 vs 0.71 h, respectively). Furthermore, oseltamivir maximum plasma concentration (Cmax) and AUC(inf) were 52% and 80% higher, respectively, in the very elderly compared with the young subjects. Oral clearance was 45% lower in elderly patients, possibly due to the effects of administration of oseltamivir with a meal. For the active metabolite, oseltamivir carboxylate, Cmax and AUC(inf) values were, respectively, 22% and 91% higher in the very elderly subjects than in the young subjects, while oral clearance was 50% lower in the elderly population. The increased exposure of the active metabolite is likely to correlate with an age-related decline in renal function. For both oseltamivir and the active metabolite, there was large interpatient variability in the Cmax values. The data reported here indicate that oseltamivir would be effective in both of these populations, as trough concentrations for the active metabolite at 12 and 24 hours exceeded the 50% inhibitory concentration against the neuraminidase of influenza A and B isolates by more than 50-fold. Oseltamivir was well tolerated in both groups.
Exposures (AUC(inf)) to both the parent drug and active metabolite were increased by more than 80% in the small number of very elderly subjects presented here. However, oseltamivir was well tolerated by these subjects.
Annals of Pharmacotherapy 10/2006; 40(10):1724-30. · 2.13 Impact Factor
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ABSTRACT: Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago. We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy. In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.
The Lancet Infectious Diseases 10/2006; 6(9):589-601. · 17.39 Impact Factor
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ABSTRACT: Multidrug-resistant Acinetobacter baumannii has emerged as a significant clinical problem worldwide and colistin is being used increasingly as "salvage" therapy. MICs of colistin against A. baumannii indicate its significant activity. However, resistance to colistin in A. baumannii has been reported recently. Clonotypes of 16 clinical A. baumannii isolates and ATCC 19606 were determined by pulsed-field gel electrophoresis (PFGE), and colistin MICs were measured. The time-kill kinetics of colistin against A. baumannii ATCC 19606 and clinical isolate 6 were investigated, and population analysis profiles (PAPs) were conducted. Resistance development was investigated by serial passaging with or without exposure to colistin. Five different PFGE banding patterns were found in the clinical isolates. MICs of colistin against all isolates were within 0.25 to 2 microg/ml. Colistin showed early concentration-dependent killing, but bacterial regrowth was observed at 24 h. PAPs revealed that heteroresistance to colistin occurred in 15 of the 16 clinical isolates. Subpopulations (<0.1% from inocula of 10(8) to 10(9) CFU/ml) of ATCC 19606, and most clinical isolates grew in the presence of colistin 3 to 10 microg/ml. Four successive passages of ATCC 19606 in broth containing colistin (up to 200 microg/ml) substantially increased the proportion of the resistant subpopulations able to grow in the presence of colistin at 10 microg/ml from 0.000023 to 100%; even after 16 passages in colistin-free broth, the proportion only decreased to 2.1%. This represents the first demonstration of heterogeneous colistin-resistant A. baumannii in "colistin-susceptible" clinical isolates. Our findings give a strong warning that colistin-resistant A. baumannii may be observed more frequently due to potential suboptimal dosage regimens recommended in the product information of some products of colistin methanesulfonate.
Antimicrobial Agents and Chemotherapy 09/2006; 50(9):2946-50. · 4.84 Impact Factor
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ABSTRACT: A simple high-performance liquid chromatographic (HPLC) method was developed and validated for rapid quantification of linezolid in human plasma. Protein precipitation using a mixture of 5% trichloroacetic acid and methanol (3:1, v/v) provided a straightforward method of sample preparation and the internal standard eperezolid was employed. A concentration range from 0.20 to 40.0 mg/L was utilized to construct calibration curves, and analysis of low- (0.40 mg/L), medium- (7.50 mg/L) and high-quality (25.0 mg/L) control samples revealed excellent reproducibility (<or=3.88%) and accuracy (<or=4.20%). The recovery of both linezolid and eperezolid was approximately 100%. No interference was observed at the retention times of linezolid and eperezolid from blank plasma or eight commonly used antibiotics. Tests confirmed the stability of linezolid in plasma during three freeze-thaw cycles, on the bench during 24 h and during long-term storage of frozen plasma for up to 12 weeks; in extracts it was stable in the HPLC autosampler over 12 h. Overall, this assay offers a highly simplistic approach to quantifying linezolid in plasma, and would be well suited to clinical pharmacokinetic, pharmacodynamic and toxicodynamic analyses.
Biomedical Chromatography 08/2006; 20(8):782-6. · 1.97 Impact Factor
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ABSTRACT: There is a dearth of information on the pharmacodynamics of "colistin," despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., approximately 0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving "colistin," in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.
Antimicrobial Agents and Chemotherapy 07/2006; 50(6):1953-8. · 4.84 Impact Factor
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Southern Medical Journal 01/2006; 98(12):1229-30. · 0.83 Impact Factor
