Models for describing absorption rate and estimating extent of bioavailability: Application to cefetamet pivoxil

Holford, Nicholas H. G.; Ambros, R J; Stoeckel, Klaus

doi:10.1007/bf01061464

Cited by 40 publications

(24 citation statements)

References 11 publications

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“…Under these conditions, the low aqueous solubility of efavirenz may limit absorption, and patient variability in water content, native surfactants, and coingested food or medications, among other factors, may influence the rate and extent of absorption during intestinal transit (50,51). Consistent with our observations, sequential zero-and first-order absorption models have best described the absorption of other compounds with suspected dissolution-limited absorption (52,53). Dissolution-limited absorption of efavirenz may account for the reported nondose proportionality of C max for oral doses ranging from 100 to 1,600 mg (11).…”

Section: Discussionsupporting

confidence: 77%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6. While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero-and firstorder processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.) KEYWORDS body composition, cytochrome P450 2B6 (CYP2B6), efavirenz, population pharmacokinetics E favirenz is a nonnucleoside reverse transcriptase inhibitor that is used in combination with nucleoside/nucleotide reverse transcriptase inhibitors to treat HIVinfected individuals older than 3 years who are naive to antiretroviral drugs. Due to its proven efficacy and low cost relative to newer antiretrovirals, efavirenz-based therapy remains the preferred first-line regimen in many low-income nations and is consequently one of the most commonly prescribed antiretroviral drugs (1). Efavirenz pharmacokinetics (PK) is characterized by large interindividual variability in plasma concentrations following a single dose (2, 3) and during chronic administration (4), which has important clinical implications. During the induction phase, efavirenz exposure is associated with central nervous system and psychiatric adverse events, liver enzyme elevation, and rash, among others (5, 6). This may result in increasing rates of

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Section: Discussionsupporting

confidence: 77%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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“…The value of CL, together with the small apparent volume of Different absorption models were fitted to the data [15][16][17] and, distribution, is responsible for the rapid decline in serum lanreofinally, a modification of the standard first-order input model, tide concentrations following an intravenous bolus injection. [20] where the absorption rate decreases exponentially as a function of When lanreotide was injected as extended-release formulations, the natural logarithm of time, was selected.…”

Section: Discussionmentioning

confidence: 99%

“…Different absorption models, [15] including time-dependent absorption rate constants (ka), the A previously validated radioimmunoassay (RIA) procedure Weibull model [16] and the transit compartment model, [17] were was used to determine serum lanreotide concentrations. [9] The tested to describe the absorption process after administration of lower limit of quantification was 0.078 ng/mL, and the overall lanreotide Autogel ® .…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects

Trocóniz¹,

Cendros²,

Peraire³

et al. 2009

Clinical Pharmacokinetics

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Abstractneuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustainedrelease formulation lanreotide Autogel ® after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose. Subjects and methods:This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 µg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel ® at a dose of 60, 90 or 120 mg. Pharmacokinetic and statistical analysis: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4-to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel ® . Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM ® version VI software. The model was validated externally using data from patients with acromegaly. Results: In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel ® 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel ® pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel ® was 63%. The rate of absorption and bioavailability of lanreotide Autogel ® were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05). Conclusions: Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 µg/kg) and the pharmacokinetics of lanreotide Autogel ® after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel ® to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel ® was independent of the dose and was not affected by sex. Backgroundmeters, the design included a rapid intravenous bolus injection of an immediate-release formulation of lanreotide (lanreotide IRF).

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“…Other scheduled meals included a standardized lunch and dinner at 6 or 12 h postdose. At each visit a 20-ml blood sample was collected prior to drug administration, and 10-ml samples were collected 2, 3,4,5,6,7,8,10,12,14,24,36, 48, and 72 h after the dose to obtain plasma for quantification of RFP and 25-DRFP. Each dose was separated by a 14-day washout period.…”

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confidence: 99%

Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers

Zvada

Walt

Smith

et al. 2010

Antimicrob Agents Chemother

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Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.Rifapentine (RFP), a cyclopentyl rifamycin, is an orally administered drug registered by the Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis (TB). It exerts its antibacterial activity through inhibition of DNAdependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis (32). RFP has a microbiologically active metabolite, 25-desacetyl rifapentine (25-DRFP) (10). RFP has a long half-life (5, 17) and superior in vitro potency against M. tuberculosis in comparison with rifampin and rifabutin (10), making it an attractive candidate for shortening and simplifying antitubercular therapy.Currently, RFP is dosed at 600 mg either once weekly or twice weekly in human immunodeficiency virus (HIV)-negative patients with noncavitary TB (2). There is concern that the development of acquired rifamycin monoresistance (ARR), treatment failure, and relapse may be associated with intermittent dosing (4, 20), insufficient companion drug exposure (33), or low rifamycin concentrations (9, 21). RFP's sterilizing effect has been shown to be dose dependent in murine studies which suggest that daily doses of RFP may reduce treatment duration to just 3 months (25,26,37), and higher doses of RFP are associated with improved early bactericidal activity in humans (29). Clinical trials are currently evaluating new antituberculosis regimens containing higher doses of RFP used intermittently or daily doses of RFP. Concomitant food has a marked effect on RFP absorption (6). The effect of food on systemic RFP exposure may therefore impact treatment activity and safety. The aim of this study was to investigate the effect of meals differing in fat and bulk content on the rate and extent of RFP absorption and 25-DRFP disposition. The ...

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Models for describing absorption rate and estimating extent of bioavailability: Application to cefetamet pivoxil

Cited by 40 publications

References 11 publications

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects

Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers

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