ABSTRACT
Desialylation of platelets results in platelet clearance by the Ashwell-Morrell Receptors (AMR) found on hepatocytes. Studies suggest that oseltamivir phosphate inhibits human sialidases, enzymes responsible for desialylation, extending the lifespan of circulating platelets. We thus evaluated, the effects of oseltamivir on platelet count (PC) following treatment. Of the 385 patients evaluated for influenza, 283 (73.5%) were influenza-infected. Of the 283 infected patients, 241 (85.2%) received oseltamivir (I + O+) while 42 patients did not (I + O-). One hundred two non-infected patients received oseltamivir (I-O+). The two groups receiving oseltamivir (I + O+, I-O+), demonstrated a statistically greater increase in the PC (57.53 ± 93.81, p = .013 and 50.79 ± 70.59, p = .023, respectively) relative to the group that did not (18.45 ± 89.33 × 109/L). The observed increase in PC was statistically similar (p = .61) in both groups receiving oseltamivir (I + O+, I-O+), suggesting that this effect is independent of influenza. Comparing clinical characteristics between responders and non-responders to oseltamivir treatment showed that only duration of oseltamivir treatment (AOR = 1.30, 95% CI 1.05-1.61, p = .015) was associated with a positive PC response. Our findings suggest a correlation between oseltamivir treatment and an increase in PCs. Future studies assessing the possible uses of oseltamivir in medical conditions characterized by diminished or defective thrombopoiesis are warranted.
Subject(s)
Oseltamivir/blood , Platelet Count/methods , Aged , Humans , Middle Aged , Retrospective StudiesABSTRACT
Oseltamivir is an antiviral drug approved to treat influenza in humans. Although the dosing regimen of this drug is well established for non-pregnant patients, it is not clear if the significant physiological alterations associated with pregnancy affect the pharmacokinetics of oseltamivir and, thus, warrant different dosing regimens to assure efficacy. In this study, we investigated the suitability of rhesus macaques as an animal model for studying oseltamivir pharmacokinetics during all trimesters of pregnancy in comparison to pre-pregnant conditions. Specifically, we compared the pharmacokinetics of oseltamivir and its pharmacologically active metabolite oseltamivir carboxylate in rhesus monkeys after intravenous and nasogastric administration of 2.5 mg oseltamivir phosphate/kg body weight given prior to and during the first, second, and third trimesters of pregnancy. Pregnancy had only a modest effect upon the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate. Monkeys treated intravenously in the third trimester had a reduction in Vd and CL, compared to non-pregnant monkeys. These changes did not occur in the other two trimesters. Pregnant monkeys treated intravenously had 20-25% decrease in AUC0-∞ of oseltamivir carboxylate and a corresponding increase in Vd and CL. Pregnant monkeys treated nasogastrically with oseltamivir phosphate demonstrated a pattern that recapitulated intravenous dosing. Taken together these data indicate that rhesus monkeys are an acceptable model for studying drug-pregnancy interactions.
Subject(s)
Antiviral Agents/pharmacokinetics , Oseltamivir/analogs & derivatives , Phosphorous Acids/pharmacokinetics , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Dose-Response Relationship, Drug , Female , Injections, Intravenous , Intubation, Gastrointestinal , Macaca mulatta , Molecular Conformation , Oseltamivir/administration & dosage , Oseltamivir/blood , Oseltamivir/pharmacokinetics , Phosphorous Acids/administration & dosage , Phosphorous Acids/blood , PregnancyABSTRACT
BACKGROUND: Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. METHODS: In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. RESULTS: Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. CONCLUSIONS: Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. CLINICAL TRIALS REGISTRATION: NCT02342249, 2014-004068-39, and CR107745.
Subject(s)
Antiviral Agents/therapeutic use , Influenza A virus , Influenza, Human/drug therapy , Oseltamivir/therapeutic use , Pyridines/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Acute Disease , Adult , Antiviral Agents/adverse effects , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , Diarrhea/chemically induced , Double-Blind Method , Drug Resistance, Viral/genetics , Drug Therapy, Combination , Early Termination of Clinical Trials , Female , Humans , Influenza A virus/genetics , Influenza A virus/physiology , Influenza, Human/virology , Male , Middle Aged , Oseltamivir/blood , Pyridines/adverse effects , Pyridines/blood , Pyridines/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Pyrroles/adverse effects , Pyrroles/blood , Pyrroles/pharmacokinetics , Time Factors , Viral Load , Viral Proteins/genetics , Virus SheddingABSTRACT
The aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and intravenous administration in rats. Only 2% of prodrug was converted into active moiety presystematically, attesting to a low advantage of oseltamivir phosphate nebulization, suggesting that oseltamivir phosphate nebulization is not a good option to obtain a high exposure of the active moiety at the infection site within lung.
Subject(s)
Oseltamivir/analogs & derivatives , Oseltamivir/pharmacokinetics , Prodrugs/pharmacokinetics , Administration, Intravenous , Animals , Male , Oseltamivir/administration & dosage , Oseltamivir/blood , Oseltamivir/pharmacology , Phosphates , Prodrugs/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and CES2 abundance (in picomoles per milligram total protein) increased approximately 5-fold (315.2 vs. 1664.4) and approximately 3-fold (59.8 vs. 174.1) from neonates to adults, respectively. CES1 protein abundance in liver cytosol also showed age-dependent maturation. Oseltamivir carboxylase activity was correlated with protein abundance in pediatric and adult liver microsomes. The protein abundance data were then used to model in vivo PK of oseltamivir in infants using pediatric physiologically based PK modeling and incorporating the protein abundance-based ontogeny function into the existing pediatric Simcyp model. The predicted pediatric area under the curve, maximal plasma concentration, and time for maximal plasma concentration values were below 2.1-fold of the clinically observed values, respectively.
Subject(s)
Aging/metabolism , Carboxylesterase/metabolism , Carboxylic Ester Hydrolases/metabolism , Liver/enzymology , Models, Biological , Oseltamivir/pharmacokinetics , Adult , Chromatography, Liquid , Cytosol/drug effects , Cytosol/enzymology , Humans , In Vitro Techniques , Infant , Liver/drug effects , Liver/growth & development , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Oseltamivir/blood , Proteomics , Tandem Mass SpectrometryABSTRACT
A simple and sensitive spectrofluorimetric method has been developed and validated for determination of oseltamivir phosphate (OSP). The proposed method is based on condensation reaction of the primary amino group of OSP with ninhydrin and phenylacetaldehyde in buffered medium (pH 6.5). The formed yellow fluorescent product exhibits excitation and emission maxima at 390 and 460 nm, respectively. The selectivity improvement of our proposed method is based on the water insolubility of the oseltamivir carboxylic acid (OSC) the active metabolite of OSP, which contains the same primary amino group as OSP but cannot, condensed with ninhydrin and phenylacetaldehyde reagents. The different experimental parameters affecting the formation and stability of the reaction product were carefully studied and optimized. The fluorescence intensity concentration plot is rectilinear in the range of 2-15 µg ml-1 with detection and quantitation limits of 0.32 and 0.98 µg ml-1, respectively. The proposed method was successfully applied for determination of OSP in commercial capsules, suspension and spiked human plasma with good percentage recovery. In addition, the developed procedure was extended to study the stability of OSP under different stress conditions; including acid and alkali hydrolysis, oxidation, photolysis, and thermal degradation. Furthermore, the kinetic of alkaline and acidic degradation of the cited drug were investigated. The apparent first order degradation rate constants were 0.258 and 0.318 K h-1 with half times of 2.68 and 2.17 h, for acidic and alkaline degradation, respectively.
Subject(s)
Antiviral Agents/blood , Capsules/analysis , Oseltamivir/blood , Phosphates/blood , Spectrometry, Fluorescence/methods , Fluorescence , Humans , Oxidation-ReductionABSTRACT
Oseltamivir is a substrate of P-glycoprotein, an efflux drug transporter encoded by ABCB1. The objective of this study was to assess the role of ABCB1 (c.1236C>T, c.2677G>T/A, and c.3435C>T) polymorphisms in the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate in humans. Nineteen healthy male subjects were enrolled, and their ABCB1 polymorphisms were evaluated. After the oral administration of 75 mg oseltamivir, the plasma concentrations of oseltamivir and oseltamivir carboxylate were measured. Pharmacokinetic analysis was carried out. Systemic exposure to oseltamivir and oseltamivir carboxylate was higher in the mutant group than in the wild-type and heterozygous groups. We suggest that ABCB1 polymorphisms affect the pharmacokinetics of oseltamivir in humans. Further studies in a large population are necessary to validate the results of this preliminary study (Clinical Trial Registration Information [CRIS] registry: http://cris.nih.go.kr, No. KCT0001903).
Subject(s)
Oseltamivir/pharmacokinetics , Pharmacogenomic Variants , ATP Binding Cassette Transporter, Subfamily B/genetics , Administration, Oral , Adult , Alleles , Chromatography, High Pressure Liquid , Genotype , Half-Life , Heterozygote , Humans , Male , Oseltamivir/blood , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Tandem Mass SpectrometryABSTRACT
The aim of this study was to determine the biopharmaceutical characteristics of oseltamivir carboxylate (OC) after pulmonary delivery. After OC bolus and intratracheal nebulization (NEB) in rats, blood was collected and bronchoalveolar lavages (BALs) were performed. Epithelial lining fluid (ELF) concentrations were estimated from BAL fluid. The area under the curve (AUC) ratio for ELF to plasma was 842 times higher after NEB than after intravenous (i.v.) administration, indicating that OC nebulization offers a biopharmaceutical advantage over i.v. administration.
Subject(s)
Anti-Infective Agents/blood , Oseltamivir/analogs & derivatives , Administration, Inhalation , Administration, Intravenous , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/pharmacokinetics , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/pharmacokinetics , Area Under Curve , Bronchoalveolar Lavage , Male , Oseltamivir/administration & dosage , Oseltamivir/blood , Oseltamivir/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
AIMS: The aims of the present study were to compare the pharmacokinetics of oseltamivir and its active antiviral metabolite oseltamivir carboxylate in obese and non-obese individuals and to determine the effect of obesity on the pharmacokinetic properties of oseltamivir and oseltamivir carboxylate. METHODS: The population pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated in 12 obese [body mass index (BMI) ≥30 kg m(-2) ) and 12 non-obese (BMI <30 kg m(-2) ) Thai adult volunteers receiving a standard dose of 75 mg and a double dose of 150 mg in a randomized sequence. Concentration-time data were collected and analysed using nonlinear mixed-effects modelling. RESULTS: The pharmacokinetics of oseltamivir and oseltamivir carboxylate were described simultaneously by first-order absorption, with a one-compartment disposition model for oseltamivir, followed by a metabolism compartment and a one-compartment disposition model for oseltamivir carboxylate. Creatinine clearance was a significant predictor of oseltamivir carboxylate clearance {3.84% increase for each 10 ml min(-1) increase in creatinine clearance [95% confidence interval (CI) 0.178%, 8.02%]}. Obese individuals had an approximately 25% (95% CI 24%, 28%) higher oseltamivir clearance, 20% higher oseltamivir volume of distribution (95% CI 19%, 23%) and 10% higher oseltamivir carboxylate clearance (95% CI 9%, 11%) compared with non-obese individuals. However, these altered pharmacokinetic properties were small and did not change the overall exposure to oseltamivir carboxylate. CONCLUSIONS: The results confirmed that a dose adjustment for oseltamivir in obese individuals is not necessary on the basis of its pharmacokinetics.
Subject(s)
Obesity/metabolism , Oseltamivir/analogs & derivatives , Oseltamivir/pharmacokinetics , Volunteers , Adolescent , Adult , Female , Humans , Male , Middle Aged , Models, Biological , Oseltamivir/blood , Young AdultABSTRACT
A simple, precise, and rapid method to simultaneously determine the levels of oseltamivir (OS) and oseltamivir carboxylate (OSC) in human plasma was developed. Additionally, the stability of both substances in plasma was investigated under different conditions. The method involved protein precipitation (0.01 % HCl in acetonitrile), and then the supernatant was injected into the high-performance liquid chromatography (HPLC)-MS/MS. The chromatographic separation was achieved on a YMC-Triart C18 (100 × 2.0 mm, 5 µm) column using acetonitrile/water (30:70, v/v) containing 0.1 % formic acid as the mobile phase. Sample volume was 5 µl. The linearity of the method was established in the concentration range of 0.5-100 ng/mL for OS and 1.0-1000 ng/mL for OSC. The intra-day precision and accuracy for oseltamivir were 1.5-8.9 and 94.4-101.0 %, respectively. For oseltamivir carboxylate, the intra-day precision and accuracy were 3.2-12.7 and 92.8-108.8 %, respectively, whereas the inter-day precision and accuracy were 5.5-11.5 and 94.6-104.0 % for oseltamivir and 4.7-11.5 and 99.9-103.9 % for oseltamivir carboxylate, respectively. The application of this method was demonstrated by a bioequivalence study in 28 healthy humans with 75 mg oseltamivir phosphate capsules (Tamiflu®). Sodium fluoride (2.4 mg/mL) with potassium oxalate (3 mg/mL) was used as anticoagulant within sampling of trial. The assay reproducibility was established by reanalysis of 80 incurred samples.
Subject(s)
Antiviral Agents/pharmacokinetics , Oseltamivir/pharmacokinetics , Therapeutic Equivalency , Antiviral Agents/blood , Chromatography, High Pressure Liquid/methods , Humans , In Vitro Techniques , Limit of Detection , Oseltamivir/blood , Reproducibility of Results , Tandem Mass Spectrometry/methodsABSTRACT
End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.
Subject(s)
Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Oseltamivir/analogs & derivatives , Renal Dialysis , Adolescent , Adult , Aged , Female , Humans , Kidney Failure, Chronic/therapy , Male , Middle Aged , Models, Theoretical , Oseltamivir/blood , Oseltamivir/therapeutic use , Young AdultABSTRACT
AIMS: Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. METHODS: A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. RESULTS: The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy. CONCLUSION: Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women.
Subject(s)
Antiviral Agents/pharmacokinetics , Oseltamivir/analogs & derivatives , Oseltamivir/pharmacokinetics , Adolescent , Adult , Antiviral Agents/blood , Computer Simulation , Female , Humans , Middle Aged , Models, Biological , Oseltamivir/blood , Pregnancy , Young AdultABSTRACT
OBJECTIVE: Critically ill children with influenza may be unable to swallow or absorb oral drugs. An intravenous (IV) formulation of the antiviral oseltamivir was evaluated in two prospective open-label studies. METHODS: Hospitalized children aged <1 year (NCT01053663) or 1-12 years (NCT01033734) with clinical or laboratory-confirmed influenza, normal renal function, and who are unable to tolerate and/or absorb oral medication were enrolled. Patients received oseltamivir 2-3 mg/kg (age<1 year) or 2.5-3 mg/kg (max. 100 mg; age 1-12 years) by slow IV infusion twice daily for up to 6 days. Blood samples were taken for pharmacokinetics and nasal swabs taken to monitor viral shedding and resistance (by reverse transcriptase polymerase chain reaction (RTPCR) and culture). Adverse events (AEs) were monitored for 30 days from treatment initiation. RESULTS: 17 children were enrolled (9 aged<1 year; 8 aged 1-12 years). On day 1, 11 patients had laboratory-confirmed influenza. Seven patients switched from IV to oral dosing before the 10th dose. Individual plasma oseltamivir carboxylate exposures (AUClast) ranged from 1,700 to 11,500 h x ng/mL. 23 AEs were reported in 10 patients; 2 were considered treatment-related (rash, infusion site erythema). Eight serious AEs (SAEs) were reported in 7 patients, including 3 deaths in patients aged <1 year; none were considered treatment-related. Two SAEs caused treatment withdrawal. Six patients had influenza detected on or after day 11 of treatment. The oseltamivir resistance mutation H275Y was detected in three samples from 1 patient with H1N1pdm09 infection. CONCLUSIONS: IV oseltamivir was well tolerated in this sample of seriously ill children. The small patient numbers precluded any formal analysis by age group or dose.
Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Influenza, Human/drug therapy , Orthomyxoviridae/drug effects , Oseltamivir/administration & dosage , Oseltamivir/pharmacokinetics , Age Factors , Antiviral Agents/adverse effects , Antiviral Agents/blood , Child , Child, Preschool , Drug Administration Schedule , Drug Resistance, Viral , Female , Hospitalization , Humans , Infant , Infant, Newborn , Influenza, Human/diagnosis , Infusions, Intravenous , Male , Orthomyxoviridae/genetics , Orthomyxoviridae/pathogenicity , Oseltamivir/adverse effects , Oseltamivir/blood , Patient Safety , Prospective Studies , Risk Assessment , Risk Factors , Treatment Outcome , United States , Viral Load , Virus SheddingABSTRACT
Oseltamivir is the most widely used anti-influenza drug. In the 2009 H1N1 pandemic, in which the influenza viruses were oseltamivir sensitive, obesity was identified as a risk factor for severe disease and unfavorable outcomes. The aim of this study was to investigate the pharmacokinetic properties of oseltamivir and its active metabolite, oseltamivir carboxylate, in obese and nonobese healthy subjects. A single-dose, randomized, two-sequence crossover study was conducted in 12 obese and 12 nonobese healthy Thai volunteers. Each volunteer was given 75 mg and 150 mg oseltamivir orally with an intervening washout period of more than 3 days. The pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated using a noncompartmental approach. The median (range) body mass indexes (BMIs) for obese subjects were 33.8 kg/m(2) (30.8 to 43.2) and 22.2 (18.8 to 24.2) for nonobese subjects. The pharmacokinetic parameters of oseltamivir carboxylate, the active metabolite of oseltamivir, were not significantly different between obese and nonobese subjects for both 75-mg and 150-mg doses. Both doses were well tolerated. Despite the lower dose per kilogram body weight in obese subjects, there was no significant difference in the exposure of oseltamivir carboxylate between the obese and nonobese groups. Standard dosing is appropriate for obese subjects. (The study was registered at ClinicalTrials.gov under registration no. NCT 01049763.).
Subject(s)
Antiviral Agents/pharmacokinetics , Obesity/metabolism , Oseltamivir/pharmacokinetics , Administration, Oral , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Body Mass Index , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Oseltamivir/administration & dosage , Oseltamivir/analogs & derivatives , Oseltamivir/blood , Thailand , Young AdultABSTRACT
There are relatively few data reported on specific features of drug pharmacokinetics (PK) and pharmacodynamics in pregnancy compared to the non-pregnant state. Changes in maternal physiology and metabolic processes during pregnancy effect on PK and show that standard adult dosing is likely to be incorrect during pregnancy. Physiology-based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women and to correctly predict drug exposure and response on the personal level.
Subject(s)
Antiviral Agents/pharmacokinetics , Influenza, Human/blood , Influenza, Human/drug therapy , Models, Statistical , Oseltamivir/pharmacokinetics , Antiviral Agents/blood , Antiviral Agents/pharmacology , Biological Availability , Biotransformation , Blood Proteins/metabolism , Carrier Proteins/metabolism , Drug Administration Schedule , Drug Dosage Calculations , Female , Humans , Influenza A Virus, H1N1 Subtype/drug effects , Influenza, Human/virology , Oseltamivir/blood , Oseltamivir/pharmacology , Pregnancy , Protein BindingABSTRACT
BACKGROUND: It is unclear if higher-dose oseltamivir provides benefit beyond the standard dose in influenza patients who require hospitalization. METHODS: A prospective intervention study was performed in 2 acute care general hospitals in Hong Kong over 4 seasonal peaks (2010-2012). Adults (≥18 years) with laboratory-confirmed influenza (85 A/H3N2, 34 A/H1N1pdm09, 36 B) infections who presented within 96 hours were recruited. Study regimen of either 150 mg or 75 mg oseltamivir twice daily for 5 days was allocated by site, which was switched after 2 seasons. Subjects with preexisting renal impairment (creatinine clearance, 40-60 mL/minute) received 75 mg oseltamivir twice daily. Viral clearance by day 5 and clinical responses were compared between groups. Plasma steady-state trough oseltamivir carboxylate (OC) concentration was measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Altogether, 41 and 114 patients received 150 mg and 75 mg twice-daily oseltamivir, respectively; their enrollment characteristics (mean age, 61 ± 18 vs 66 ± 16 years) and illness severity were comparable. Trough OC levels were higher in the 150-mg group (501.0 ± 237.0 vs 342.6 ± 192.7 ng/mL). There were no significant differences in day 5 viral RNA (44.7% vs 40.2%) or culture negativity (100.0% vs 98.1%), RNA decline rate, and durations of fever, oxygen supplementation, and hospitalization. Results were similar when analyzed by study arm (all cases and among those without renal impairment). Subanalysis of influenza B patients showed faster RNA decline rate (analysis of variance, F = 4.14; P = .05) and clearance (day 5, 80.0% vs 57.1%) with higher-dose treatment. No oseltamivir resistance was found. Treatments were generally well tolerated. CONCLUSIONS: We found no additional benefit of higher-dose oseltamivir treatment in adults hospitalized with influenza A, but an improved virologic response in influenza B. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT01052961.
Subject(s)
Antiviral Agents/administration & dosage , Influenza A virus/isolation & purification , Influenza B virus/isolation & purification , Influenza, Human/drug therapy , Influenza, Human/virology , Oseltamivir/administration & dosage , Aged , Aged, 80 and over , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , Female , Hong Kong/epidemiology , Hospitalization , Humans , Influenza, Human/epidemiology , Male , Middle Aged , Nasopharynx/virology , Oseltamivir/blood , Oseltamivir/pharmacokinetics , Prospective Studies , Treatment Outcome , Viral LoadABSTRACT
Oseltamivir and oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous-blood-to-plasma ratios were 1.42 (0.920 to 1.97) for oseltamivir and 0.673 (0.564 to 0.814) for oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737 to 3.16) for oseltamivir and 0.685 (0.502 to 1.34) for oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood.
Subject(s)
Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , Oseltamivir/analogs & derivatives , Oseltamivir/blood , Oseltamivir/pharmacokinetics , Capillaries , Female , Humans , Male , PlasmaABSTRACT
Oseltamivir carboxylate (OC) has been detected in environmental waters at various levels during recent influenza seasons in humans, reflecting levels of usage and stability of this drug. In consideration of the role of waterfowl as hosts for influenza viruses that may contribute to human infections, we evaluated the effect of consumption of low doses of OC on development of oseltamivir-resistant influenza virus mutants in mallard ducks (Anas platyrhynchos) infected with two different low-pathogenic (LP) H5N2 avian influenza viruses (AIV). We detected development of virus variants carrying a known molecular marker of oseltamivir resistance (neuraminidase E119V) in 4 out of 6 mallards infected with A/Mallard/Minnesota/182742/1998 (H5N2) and exposed to 1,000 ng/liter OC. The mutation first appeared as a minor population on days 5 to 6 and was the dominant genotype on days 6 to 8. Oseltamivir-resistant mutations were not detected in virus from ducks not exposed to the drug or in ducks infected with a second strain of virus and similarly exposed to OC. Virus isolates carrying the E119V mutation displayed in vitro replication kinetics similar to those of the wild-type virus, but in vivo, the E119V virus rapidly reverted back to wild type in the absence of OC, and only the wild-type parental strain was transmitted to contact ducks. These results indicate that consumption by wild waterfowl of OC in drinking water may promote selection of the E119V resistance mutation in some strains of H5N2 AIV that could contribute to viruses infecting human populations.
Subject(s)
Antiviral Agents/pharmacology , Ducks/virology , Environmental Pollutants/pharmacology , Influenza A Virus, H5N2 Subtype/drug effects , Influenza in Birds/virology , Neuraminidase/genetics , Oseltamivir/analogs & derivatives , Viral Proteins/genetics , Animals , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , Drug Resistance, Viral/drug effects , Environmental Pollutants/blood , Environmental Pollutants/pharmacokinetics , Influenza A Virus, H5N2 Subtype/enzymology , Influenza A Virus, H5N2 Subtype/genetics , Influenza in Birds/transmission , Mutation , Neuraminidase/metabolism , Oseltamivir/blood , Oseltamivir/pharmacokinetics , Oseltamivir/pharmacology , Viral Load , Viral Proteins/metabolism , Virus ReplicationABSTRACT
We conducted a 2-sample pharmacokinetic study of oseltamivir in 12 premature infants. Oseltamivir 1 mg/kg/dose twice daily in infants <38 weeks postmenstrual age (n=8) resulted in oseltamivir carboxylate exposure comparable to previously published pediatric data, which helps prospectively validate this regimen. Oseltamivir 3 mg/kg/dose once daily in premature infants >38 weeks postmenstrual age (born prematurely but chronologically past term, n=4) resulted in similar oseltamivir and oseltamivir carboxylate exposure. Although these results suggest persistence of immature renal function in this subgroup, further pharmacokinetic/pharmacodynamic description is required to confirm the appropriateness of this regimen.
Subject(s)
Antiviral Agents/pharmacokinetics , Infant, Premature/metabolism , Oseltamivir/pharmacokinetics , Absorption , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Area Under Curve , Drug Administration Schedule , Humans , Infant, Newborn , Kidney/growth & development , Kidney/metabolism , Models, Biological , Oseltamivir/administration & dosage , Oseltamivir/blood , Prospective StudiesABSTRACT
There is an unmet need for an intravenous (i.v.) neuraminidase inhibitor, particularly for patients with severe influenza who cannot take oral medication. Two phase I pharmacokinetic and safety studies of i.v. oseltamivir were carried out in healthy volunteers. The first was an open-label, randomized, four-period, two-sequence, single-dose trial of 100 mg, 200 mg, and 400 mg oseltamivir i.v. over 2 h and a 75-mg oral dose of oseltamivir. The second was a double-blind, placebo-controlled, parallel-group, multiple-dose study in which participants were randomized to 100 mg or 200 mg oseltamivir or placebo (normal saline) i.v. over 2 h every 12 h for 5 days. Exposure to the active metabolite oseltamivir carboxylate (OC) after dosing achieved with 100 mg oseltamivir administered i.v. over 2 h was comparable to that achieved with 75 mg administered orally. Single i.v. doses of oseltamivir up to 400 mg were well tolerated with no new safety signals. Multiple-dose data confirmed good tolerability of 100 mg and 200 mg oseltamivir and showed efficacious OC exposures with 100 mg i.v. over 2 h twice daily for 5 days. These results support further exploration of i.v. oseltamivir as an influenza treatment option for patients unable to take oral medication.