Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults: Dose Modification for Weight Is Not Necessary

ABSTRACTObesity is an independent risk factor for mortality in patients infected with pandemic influenza A virus (H1N1). Given the poor outcomes observed among adult obese patients with H1N1, the dosing of antiviral agents in this population has been questioned, and use of twice the standard oseltamivir dose has been suggested. However, studies evaluating the disposition of oseltamivir and oseltamivir carboxylate (the active metabolite) in the obese population are scant. We evaluated the single-dose and steady-state pharmacokinetics of oseltamivir (75 mg by mouth twice daily) in a cohort of 21 healthy adult volunteers with class III obesity (body mass index [BMI], ≥40 kg/m2). The median (minimum, maximum) age, weight, and BMI were 36 (19, 50) years, 122 (106, 159) kg, and 43.7 (40.0, 54.4) kg/m2, respectively. The population pharmacokinetic exposure profiles of oseltamivir carboxylate (the active metabolite) were comparable between class III obese subjects and nonobese adults (healthy and infected). Similar to previous pharmacokinetic analyses in nonobese subjects, the mean (percent covariance [CV]) area under the concentration-time curve for the dosing interval (AUC0–τ) was 2,621 ng·h/ml (17) for oseltamivir carboxylate. Body size was significantly (P< 0.05) associated with oseltamivir and oseltamivir carboxylate apparent clearance, but the correlation coefficient was poor (R2≤ 0.3). Creatinine clearance estimated by the Cockcroft-Gault method and lean body weight were also significantly (P< 0.05) but poorly (R2= 0.17) correlated with oseltamivir carboxylate apparent clearance. Since the systemic exposure of oseltamivir carboxylate is not reduced in class III obese adults with standard doses, a dose increment of oseltamivir is likely to be unnecessary.

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Development of a Population Pharmacokinetic Model for Parecoxib and Its Active Metabolite Valdecoxib after Parenteral Parecoxib Administration in Children

Anesthesiology ◽

10.1097/aln.0b013e31825154ef ◽

2012 ◽

Vol 116 (5) ◽

pp. 1124-1133 ◽

Cited By ~ 11

Author(s):

Bruce Hullett ◽

Sam Salman ◽

Sean J. O'Halloran ◽

Deborah Peirce ◽

Kylie Davies ◽

...

Keyword(s):

Active Metabolite ◽

Pharmacokinetic Model ◽

Inhibitory Concentration ◽

Prediction Interval ◽

Cyclooxygenase 2 ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Time Curve ◽

Concentration Time

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

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Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01541-08 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4753-4761 ◽

Cited By ~ 22

Author(s):

Gerhard Hoffmann ◽

Christoph Funk ◽

Stephen Fowler ◽

Michael B. Otteneder ◽

Alexander Breidenbach ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Active Transport ◽

Active Metabolite ◽

Influenza A ◽

Transport Processes ◽

Oseltamivir Carboxylate ◽

The Central Nervous System ◽

Oral Doses

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.

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Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00327-08 ◽

2008 ◽

Vol 52 (10) ◽

pp. 3687-3693 ◽

Cited By ~ 46

Author(s):

S. S. Jhee ◽

M. Yen ◽

L. Ereshefsky ◽

M. Leibowitz ◽

M. Schulte ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Influenza A ◽

Abnormal Behavior ◽

Oseltamivir Carboxylate ◽

Open Label ◽

Time Curve ◽

Open Label Study ◽

The Central Nervous System ◽

Cns Penetration ◽

Adult Volunteers

ABSTRACT Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C max], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C max, 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C max CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

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Oseltamivir Pharmacokinetics and Clinical Experience in Neonates and Infants during an Outbreak of H1N1 Influenza A Virus Infection in a Neonatal Intensive Care Unit

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00290-12 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3833-3840 ◽

Cited By ~ 17

Author(s):

Joseph F. Standing ◽

Angela Nika ◽

Vasileios Tsagris ◽

Ioannis Kapetanakis ◽

Helena C. Maltezou ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Neonatal Intensive Care Unit ◽

Influenza A ◽

Neonatal Intensive Care ◽

Pharmacokinetic Model ◽

Population Pharmacokinetic ◽

Oseltamivir Carboxylate ◽

Influenza A H1n1 ◽

Neonates And Infants

ABSTRACTDetailed oseltamivir pharmacokinetics have yet to be reported in neonates and infants; this group is at high risk of serious influenza-associated complications. Extrapolation of doses from older patients is complicated by rapid organ and drug-metabolizing enzyme maturation. A pharmacokinetic study has been conducted during an influenza A(H1N1) outbreak in a neonatal intensive care unit. Each included patient provided 4 samples for oseltamivir and 4 samples for its active metabolite oseltamivir carboxylate. A population pharmacokinetic model was developed with NONMEM. Allometric weight scaling and maturation functions were addeda priorito scale for size and age based on literature values. Nine neonates and infants were recruited. A physiologically parameterized pharmacokinetic model predicted typical day 1 area under the curve (AUC0-12) values of 1,966 and 2,484 μg · h/liter for neonates and infants of ≤37 weeks of postmenstrual age (PMA) and >37 weeks of PMA treated with 1 mg/kg of body weight and 2 mg/kg, respectively. The corresponding steady-state AUC0-12values were 3,670 and 4,559 μg · h/liter. Premature neonates treated with 1 mg/kg and term babies treated with 2 mg/kg should have average oseltamivir carboxylate concentrations in a range similar to that for adults treated with 75 mg, corresponding to >200-fold above the half-maximal inhibitory concentration (IC50) value for influenza A(H1N1) from the start of therapy.

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Population Pharmacokinetics of Fluconazole in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration: Using Monte Carlo Simulations To Predict Doses for Specified Pharmacodynamic Targets

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00424-11 ◽

2011 ◽

Vol 55 (12) ◽

pp. 5868-5873 ◽

Cited By ~ 28

Author(s):

Kashyap Patel ◽

Jason A. Roberts ◽

Jeffrey Lipman ◽

Susan E. Tett ◽

Megan E. Deldot ◽

...

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Critically Ill ◽

Systemic Exposure ◽

Kidney Injury ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Time Curve ◽

Continuous Venovenous Hemodiafiltration ◽

Fungal Organisms

ABSTRACTFluconazole is a widely used antifungal agent that is extensively reabsorbed in patients with normal renal function. However, its reabsorption can be compromised in patients with acute kidney injury, thereby leading to altered fluconazole clearance and total systemic exposure. Here, we explore the pharmacokinetics of fluconazole in 10 critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF). We performed Monte Carlo simulations to optimize dosing to appropriate pharmacodynamic endpoints for this population. Pharmacokinetic profiles of initial and steady-state doses of 200 mg intravenous fluconazole twice daily were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis and to perform Monte Carlo simulations. For each dosing regimen, the free drug area under the concentration-time curve (fAUC)/MIC ratio was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values. A two-compartment model adequately described the disposition of fluconazole in plasma. The estimate for total fluconazole clearance was 2.67 liters/h and was notably 2.3 times faster than previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CLCVVHDF) represented 62% of its total systemic clearance. Furthermore, the predicted efficiency of CLCVVHDFdecreased to 36.8% when filters were in use >48 h. Monte Carlo simulations demonstrated that a dose of 400 mg twice daily maximizes empirical treatment against fungal organisms with MIC up to 16 mg/liter. This is the first study we are aware of that uses Monte Carlo simulations to inform dosing requirements in patients where tubular reabsorption of fluconazole is probably nonexistent.

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Pharmacokinetic-Pharmacodynamic Determinants of Oseltamivir Efficacy Using Data from Phase 2 Inoculation Studies

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02440-12 ◽

2013 ◽

Vol 57 (8) ◽

pp. 3478-3487 ◽

Cited By ~ 18

Author(s):

C. R. Rayner ◽

C. C. Bulik ◽

M. A. Kamal ◽

D. K. Reynolds ◽

S. Toovey ◽

...

Keyword(s):

Influenza A ◽

Viral Titer ◽

Phase 2 ◽

Oseltamivir Carboxylate ◽

Individual Values ◽

Time Curve ◽

Minimum Concentration ◽

Viral Shedding ◽

Exposure Response ◽

Symptom Scores

ABSTRACTGiven the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC50] = 0.18 nM) or B/Yamagata (IC50= 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC0–24), minimum concentration of OC in plasma (Cmin), and maximum concentration of OC in plasma (Cmax). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC0–24evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC0–24threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

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Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults

Pharmaceutics ◽

10.3390/pharmaceutics13040487 ◽

2021 ◽

Vol 13 (4) ◽

pp. 487

Author(s):

Saebyul Yoo ◽

Bom-I Park ◽

Do-hyun Kim ◽

Sooyoung Lee ◽

Seung-hoon Lee ◽

...

Keyword(s):

Clinical Trial ◽

Molecular Weight ◽

Absorption Rate ◽

Systemic Exposure ◽

Red Ginseng ◽

Double Blind ◽

Time Curve ◽

Concentration Time ◽

Black Ginseng ◽

Clinically Significant

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1-h faster absorption rate (Tmax) and 58% higher exposure (24-h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5-h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

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Amantadine Inhibits SARS-CoV-2 In Vitro

Viruses ◽

10.3390/v13040539 ◽

2021 ◽

Vol 13 (4) ◽

pp. 539

Author(s):

Klaus Fink ◽

Andreas Nitsche ◽

Markus Neumann ◽

Marica Grossegesse ◽

Karl-Heinz Eisele ◽

...

Keyword(s):

Influenza A ◽

Antiviral Agents ◽

Antiviral Drug ◽

Systemic Exposure ◽

Topical Administration ◽

Counter Measures ◽

Travel Restrictions ◽

Drug Treatments ◽

Intranasal Instillation

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist. However, unequivocal evidence for efficacy against SARS-CoV-2 has not been demonstrated for any of the repurposed antiviral drugs so far. Amantadine was approved as an antiviral drug against influenza A, and antiviral activity against SARS-CoV-2 has been reasoned by analogy but without data. We tested the efficacy of amantadine in vitro in Vero E6 cells infected with SARS-CoV-2. Indeed, amantadine inhibited SARS-CoV-2 replication in two separate experiments with IC50 concentrations between 83 and 119 µM. Although these IC50 concentrations are above therapeutic amantadine levels after systemic administration, topical administration by inhalation or intranasal instillation may result in sufficient amantadine concentration in the airway epithelium without high systemic exposure. However, further studies in other models are needed to prove this hypothesis.

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Lack of Effect of Ginkgo biloba on Voriconazole Pharmacokinetics in Chinese Volunteers Identified as CYP2C19 Poor and Extensive Metabolizers

Annals of Pharmacotherapy ◽

10.1345/aph.1l537 ◽

2009 ◽

Vol 43 (4) ◽

pp. 726-731 ◽

Cited By ~ 28

Author(s):

He-Ping Lei ◽

Guo Wang ◽

Lian-Sheng Wang ◽

Dong-sheng Ou-yang ◽

Hao Chen ◽

...

Keyword(s):

Single Dose ◽

Ginkgo Biloba ◽

Poor Metabolizers ◽

Pharmacokinetic Parameters ◽

Extensive Metabolizers ◽

Herbal Supplements ◽

Time Curve ◽

Concentration Time ◽

Apparent Clearance ◽

Randomized Crossover Study

Background: Ginkgo biloba is one of the most popular herbal supplements in the world. The supplement has been shown to induce the enzymatic activity of CYP2C19, the main cytochrome P450 isozyme involved in voriconazole metabolism. Because this enzyme exhibits genetic polymorphism, the inductive effect was expected to be modulated by the CYP2C19 metabolizer status. Objective: To examine the possible effects of Ginkgo biloba as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CVP2C19 extensive or poor metabolizers. Methods: Fourteen healthy, nonsmoking volunteers–7 CYP2C19 extensive metabolizers (2C19*1/2C19*1) and 7 poor metabolizers (2C19*2/2C19*2)–were selected to participate in this study. Pharmacokinetics of oral voriconazole 200 mg after administration of Ginkgo biloba 120 mg twice daily for 12 days were determined for up to 24 hours by liquid chromatography–electrospray tandem mass spectrometry in a 2-phase randomized crossover study with 4-week washout between phases. Results: For extensive metabolizers, the median value for voriconazole area under the plasma concentration–time curve from zero to infinity (AUC0-00) was 5.17 μg•h/mL after administration of voriconazole alone and 4.28 μg•/mL after voriconazole with Ginkgo biloba (p > 0.05). The other pharmacokinetic parameters of voriconazole such as AUC0-24, time to reach maximum concentration, half-life, and apparent clearance also did not change significantly for extensive metabolizers in the presence of Ginkgo biloba. Pharmacokinetic parameters followed a similar pattern for poor metabolizers. Conclusions: The results suggest that 12 days of treatment with Ginkgo biloba did not significantly alter the single-dose pharmacokinetics of voriconazole in either CYP2C19 extensive or poor metabolizers. Therefore, the pharmacokinetic interactions between voriconazole and Ginkgo biloba may have limited clinical significance.

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Sex Differences in the Effect of Testosterone on Adipose Tissue Insulin Resistance from Overweight to Obese Adults

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab325 ◽

2021 ◽

Author(s):

Xiaohui Li ◽

Jia Liu ◽

Biao Zhou ◽

Yinhui Li ◽

Zhengyu Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Sex Differences ◽

Adipose Tissue ◽

Protective Factor ◽

Class Iii ◽

Obese Adults ◽

Testosterone Levels ◽

Class Iii Obesity ◽

Males And Females ◽

Potential Factors

Abstract Objective Adipose tissue distribution and glucose metabolism differ between men and women. Few studies have investigated sex differences in adipose tissue insulin resistance (adipose-IR). Herein, we investigated sex differences in adipose-IR in adults ranging from overweight to obese and the potential factors associated with sex differences in adipose-IR. Methods A total of 424 adults had their BMI, adipose-IR, and sex hormones evaluated. Based on BMI, males and females were assigned to four groups. Results In total, males (n=156) had higher adipose-IR than females with similar BMIs (n=268) (p<0.05). Adipose-IR progressively increased from overweight to class III obesity in both males and females (all p<0.0001); however, only in the class III obesity group was the adipose-IR significantly higher in males than in females (p=0.025). There were significant differences in testosterone between males and females (all p<0.01); testosterone levels were negatively correlated with adipose-IR (r=-0.333, p<0.001) in males but positively correlated with adipose-IR (r=0.216, p<0.001) in females. For the logistic regression analysis, testosterone was an independent protective factor against adipose-IR in males, with an odds ratio of 0.858 (B= -0.153 [95% CI 0.743-0.991], p=0.037). Conclusions Adipose-IR reflects the progressive deterioration in adipose tissue insulin sensitivity from overweight to obesity in both males and females. Males with class III obesity have more severe adipose-IR than similarly obese females. The sex difference is associated with testosterone, and low testosterone levels may contribute to more severe adipose-IR in obese males.

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