The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

A method for calculating the mean absorption time of drugs undergoing reversible and first-pass metabolism

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.     

The Area Function Method for Assessing the Drug Absorption Rate in Linear Systems with Zero-Order Input

A noncompartmental approach for determination of the apparent zero-order absorption rate constant (k ₀) has been developed. The procedure evolves from the convolution integral and requires individual oral-dose plasma concentration values and calculation of area intervals under the plasma concentration–time curves after intravenous administration. The proposed method was evaluated and compared with the Wagner–Nelson, Loo–Riegelman, deconvolution, nonlinear regression, and moment methods using errorless and errant simulation data for one- or two-compartment models. The area function method is generally equal to the best of these techniques (nonlinear regression) and superior to the weaker methods (moment, deconvolution, Loo–Riegelman), especially for errant two-compartment data. Coupled with a companion procedure for constructing fraction absorbed versus time plots and assessing first-order absorption rate constants, the area function methods offer direct and accurate means of discerning drug absorption kinetics without the need for assignment of a disposition model for drugs with linear elimination kinetics.     

Constant-Rate Intravenous Infusion Methods for Estimating Steady-State Volumes of Distribution and Mean Residence Times in the Body for Drugs Undergoing Reversible Metabolism

Equations for the steady-state volumes of distribution (V _ss) and the mean residence times in the body (MRT) are derived for a drug and its metabolite subject to reversible metabolism and separately infused intravenously at a constant rate to steady state of both compounds. The V _ss and MRT parameters are functions of the integrals of plasma concentrations, plasma concentrations at steady state, and times to reach steady state of both drug and metabolite. In addition, the MRT values are functions of the infusion rates. These equations were validated by computer simulations and comparison with IV bolus dose parameters. These relationships extend the ability to assess the pharmacokinetics of linear reversible metabolic systems.     

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast sodium (MK-0476), 10 mg d⁻¹ in healthy young subjects (N =12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N =12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d⁻¹ (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration–time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL⁻¹ on days 3–7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1·14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (V_ss), plasma terminal half-life (t_1/2), and mean residence time in the body (MRT^IV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30·8 mL min⁻¹, 9·7 L, 6·7 h, and 5·4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC_0→∞, C_max, t_max, and t_1/2, and the mean plasma concentration–time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age. © 1997 John Wiley & Sons, Ltd.     

PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5–90 μg kg⁻¹of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 μg kg⁻¹ are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 μg kg⁻¹. The values of the plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_½), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min⁻¹, 140 L, 1·8 h, and 1·7 h, respectively, and remained essentially constant over the dosage range of 10–60 μg kg⁻¹ of IV MK-462. However, as the dose increased from 60 to 90 μg kg⁻¹, the mean value of the apparent CL decreased from 1376 to 807 mL min⁻¹. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V_ss value of MK-462 remained essentially constant over the dosage range of 10–90 μg kg⁻¹ of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL_d=2028 mL min⁻¹, and mean transit time in the peripheral tissues (MTT_T )=0·74 h. The mean values of AUC, C_max, t_max, and apparent t_½ of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng·h mL⁻¹, 77 ng mL⁻¹, 1·6 h, and 1·8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by ≈20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C_max and apparent t_½ of MK-462.     

Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics

A two-compartment closed model was used to characterize the movement of basophils between blood and extravascular sites resulting from methylprednisolone (MP) exposure. This model is consistent with the view that corticosteroids cause a decrease in the recirculation of these cells from peripheral compartments. Methylprednisolone (Solu-Medrol) was given to healthy males at doses of 10, 25, and 40 mg. Blood samples were collected and assayed for MP by HPLC for pharmacokinetic analysis. Whole blood histamine, an index of circulating basophils, was assessed by RIA over 32 hr. Nonlinear least-squares analysis was carried out to solve for the model parameters reflecting cell movement between compartments and sensitivity (IC₅₀)to the steriod. This model quantitates the fall and return pattern of biologic response to corticosteroids with a minimal number of parameters which jointly fit several dose/response curves and yields a mean IC₅₀ value of 8.1 ng/ml similar to receptor binding of MP. Properties of the temporal and integrated response curve and model extrapolations over a wide dose range were explored with simulations. Because corticosteroids exert similar effects on other cells in blood, this model may be applicable to various regulatory and immunosuppressive effects.This work was supported in part by Grants GM 24211 and 150-1885-0 from the National Institute of General Medical Sciences, NIH.