Pharmacokinetic model equations for the one- and two-compartment models with first-order processes in which the absorption and exponential elimination or distribution rate constants are equal

Tenofovir is a nucleotide analogue used as a combination therapy with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. To be active, tenofovir needs to be converted at the intracellular level to tenofovir diphosphate, which inhibits the viral reverse transcriptase (10). A pharmacokinetic study performed after intravenous administrations of tenofovir in HIV-infected adults (5) has shown that 70 to 80% of the dose was recovered unchanged in urine and that tubular secretion was an important pathway for tenofovir clearance. A significant increase in tenofovir exposure was also demonstrated in adult patients with creatinine clearance (CL CR ) less than 50 ml/min, which required a decrease in tenofovir dosage regimen for this subpopulation (10). For adult patients with CL CR greater than 50 ml/min, the same dosage regimen of 300 mg once a day (QD) of tenofovir disoproxil fumarate (TDF), an oral prodrug of tenofovir, is recommended. However, the influence of renal function on tenofovir exposure has still not been studied in patients with CL CR greater than 50 ml/min.Thus, in order to evaluate whether a dose adjustment based on renal function could be considered for tenofovir therapy, even in patients receiving the recommended 300-mg QD dose, the influence of the renal function on tenofovir pharmacokinetics was investigated using a population approach performed retrospectively on routine therapeutic drug monitoring data. MATERIALS AND METHODSPatients and treatment. The population comprised adult patients receiving TDF, as 300-mg tablets equivalent to 245 mg of tenofovir, at its recommended 300-mg QD dose for the treatment of HIV infection and monitored according to the plasma concentrations of antiretroviral drugs on a routine basis. For each patient, time elapsed between administration and sampling times, gender, body weight (BW), and age were carefully recorded, as well as combined treatments, particularly antiretroviral drugs. Corresponding serum creatinine (S CR ), phosphorus concentration, and viral load were obtained from routine monitoring data performed in Cochin-Saint-Vincent-de-Paul Hospital Biochemistry and Virology Departments respectively. Creatinine clearance was calculated for each sample according to the Cockroft-Gault formula (3) and the Jelliffe formula (8).Analytical methods. The tenofovir assay was performed according to a previously published method (9) with a quantification limit, interassay precision, and bias of 0.005 mg/liter, 9.6%, and 11.4%, respectively.Population pharmacokinetic modeling. Concentration-time data were analyzed using the first-order conditional estimation (FOCE) method of the nonlinear mixed effects modeling program NONMEM (2) (version V, level 1.1, double precision). Several structural pharmacokinetic models were investigated. Classical one, two, and three-compartment models were first evaluated. A twocompartment pharmacokinetic model in which the absorption (k a ) and distribution rate (␣) constants are equal was also tried (1...

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

Jullien

Tréluyer

Rey

et al. 2005

“…Furthermore, the inclusion of covariates provided high standard deviations for estimates of the values of k a and V/F 2 (where V/F 2 is the interindividual variability of V/F), suggesting that these parameters could not be estimated (data not shown). Because of these results, a limited form of this model that corresponded to a one-compartment model with first-order absorption when k a and k el are not distinguishable was used (31). This model provided the best fit, with a further 20-point decrease in the objective function compared to the value obtained by use of the classical one-compartment model.…”

Section: Resultsmentioning

confidence: 99%

“…Classical one-and two-compartment models with first-and zero-order absorption were first evaluated. A one-compartment pharmacokinetic model in which a single rate constant (k) was used for both the absorption and the elimination processes was also tried (31). The equation for this model was as follows:…”

Section: Methodsmentioning

confidence: 99%

Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

Jullien

Urien

Hirt

et al. 2006

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.Lopinavir is a protease inhibitor (PI) used for the treatment of human immunodeficiency virus (HIV) infection in children and adults. Lopinavir can be administered to children older than 6 months of age by the use of a liquid formulation as well as by the use of a solid oral formulation, both of which contain ritonavir for pharmacokinetic enhancement, at recommended lopinavir/ritonavir doses of 12/3 mg/kg of body weight (BW) twice daily (BID) for children with BWs between 7 and 14 kg and 10/2.5 mg/kg BID for children with BWs between 15 and 40 kg. For children with body weights greater than 40 kg, the 400/100-mg BID adult dosage regimen is recommended. Children younger than 6 months of age were not investigated in previously published studies (3,27). This lack of data can explain to some extent why lopinavir is not recommended for use in children younger than age 6 months. Nevertheless, there are clinical situations, such as the presence of a viral strain less sensitive to the other antiretrovirals, which could require the administration of lopinavir to very young children. Another pediatric population for which pharmacokinetic data are lacking is children with BWs greater than 40 kg. However, this lack of data for adolescents is a very common phenomenon and is relevant not only to lopinavir. Frequently, adolescents are considered similar to adults from a pharmacokinetic point of view, which explains why adolescents often receive the recommended adult dosage regimen. However, adolescence is characterized by physiological and hormonal changes (26, 30), the possible consequences of which on the pharmacokinetics and metabolism of drugs are still unknown. Because pharmacokinetic data for children younger than age 6 months and adolescents are lacking, the relationships between lopinavir pharmacokinetic parameters and the individual characteristics of children are also not known. These relationships are nevertheless important for optimization of the lopinavir dosage regimen, as several studies perform...

“…1). Thus, our study data were best described by a 2-compartment model in which the k a and the slope of the distribution rate constant (␣) were equal (13). The parameters of this model were apparent elimination clearance (CL/F), apparent intercompartmental clearance (Q/F), and apparent central (V c /F) and peripheral (V p /F) volumes of distribution, with F being the unknown bioavailability.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, as the effects of pregnancy on absorption are not well understood and pregnancy might alter drug absorption (12), we also considered a model with an absorption rate constant (k a ) equal to the distribution rate constant (␣). This model was tested according to the following equation (13):…”

mentioning

confidence: 99%

Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

Valade

Tréluyer

Bouazza

et al. 2014

The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal.