Apparent clearance

The apparent clearance (Cl/F) and the apparent volume (Vd/F) estimates are related to the bioavailability after oral dosing. 

If there is a very large within- or between-subject variability in apparent clearance this might indicate variable absorption or bioavailability, which in turn is often seen when absorption or bioavailability is low. 

Calculation of bioavailability requires a comparison of the AUcs following a non-intravenous and an intravenous dose, after correction for dose size. Without knowing the bioavaUabU-ity, only apparent clearance and volume of distribution can be calculated, and the ability to make predictions from these values is very limited. 

The apparent clearance of lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme inducing antiepileptic drugs (ElAEDs), including carbamazepine, phenytoin, phenobarbital, and primidone. 

Tablets The terminal half-life following a single dose administration is approximately 120 to 170 hours. The total apparent clearance is about 26 L/h. 

Renai/Hepatic function impairment The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency only have been evaluated after single dose administration. In a single dose study of patients with anuric renal failure, the apparent clearance was approximately 40% lower and the elimination half-life was 1.6-fold greater than that in healthy controls. In a study of 14 people with chronic liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after a single dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10 patients with severe liver dysfunction was 50% lower than that reported for healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in plasma, exercise caution when patients with renal or hepatic insufficiency are treated with rimantadine. 

Children Nevirapine apparent clearance adjusted for body weight was at least 2-fold... 

Following a single 90 mg subcutaneous dose of enfuvirtide the mean SD elimination half-life of enfuvirtide is 3.8 0.6 hours and the mean SD apparent clearance was 24.8 4.1 mL/h/kg. 

Metabolism/Excretion-The mean peginterferon alfa-2b elimination half-life is approximately 40 hours (range, 22 to 60 hours) in patients with HCV infection. The apparent clearance of peginterferon alfa-2b is estimated to be approximately 22 mL/h kg. Renal elimination accounts for 30% of the clearance. 

Pegylation of interferon alfa-2b produces a product (peginterferon alfa-2b) whose clearance is lower than that of nonpegylated interferon alfa-2b. When compared to interferon alfa-2b, peginterferon alfa-2b (1 mcg/kg) has an approximately 7-fold lower mean apparent clearance and a 5-fold greater mean half life permitting a reduced dosing frequency. 

The term apparent clearance is used because the bioavailability of the compound is unknown. Thus, estimations of apparent clearance will always be higher than the true systemic clearance because of this unknown bioavailability. 

Several [Gex-Fabry et al. 1990 Nagy and Johansson 1977], but not all [Vazquez-Rodriguez et al. 1991], research groups found that women achieve higher plasma levels of clomipramine. Some evidence shows that the apparent clearance of the hydroxylated metabolites of clomipramine is slower in women [Gex-Fabry et al. 1990]. 

Fig. 10.8. Cellular activity and hepatocyte stability of the 37 purified library compounds, (a) cLipE vs. human np-HSD1 EC50 (hHEKEC50). Chart enables rapid identification of the active and lipophilic efficient compounds (in lower right corner), e.g., PF-03440171 with cLipE = 8.7 and EC50 = 0.03 nM. (b) Fluman hepatocyte intrinsic apparent clearance (GLJiFlepCI) vs. hHEKEC50. Chart enables rapid identification of active and metabolically stable compounds, such as PF-03440142 with GLJiFlepCI = 5 pl/min/million and EC50 = 67 nM.

Elimination of tliis drug follows Michaelis-Menten kinetics. Apparent clearance will be lower when plasma levels are higher than those obtained in this study. 

In an open, crossover, randomized stndy in 12 healthy men St. John s wort significantly indnced the apparent clearance of both -warfarin and J -warfarin (by 29 and 23% respectively), which in tnrn resnlted in a significant rednc-tion in the pharmacological effect of racemic warfarin (35). 

The two enantiomers of thalidomide, R and S, undergo fast chiral interconversion at physiological pH (16). The apparent clearance rates in adults are 10 1/hour for R-thahdomide and 211/hour for 5-thalidomide however, each has a half-life of about 5 hours, impljdng different volumes of distribution (70 hters for the R-enantiomer and 150 hters for the 5-enantiomer). Because of rapid interconversion, administration of R-thahdomide alone as a hjrpnotic would not avoid the teratogenic affects of 5-thalidomide. Thalidomide does not induce its own metabohsm. Its plasma protein binding is low. 

A new molecular entity exhibiting one-compartment pharmacokinetics with first-order absorption was assumed. The typical (mean) values of the population PK parameters for the NME were 1 h 17.5L/h, and SOL for absorption rate constant (Ka), apparent clearance (CLIP), and apparent volume of distribution (V/F), respectively. An intersubject variability of 45% (coefficient of variation) was assumed for each of these parameters, and this was assumed to be lognormally distributed with a mean of zero. A proportional error model was assumed for the residual error of 15%. 

Both between-subject and interoccasion variances were estimated on clearance of nelfinavir, absorption rate constant, and clearance of M8. The residual error with a proportional error model was modeled for nelfinavir and M8 separately. The effect of ritonavir was found to have a statistically significant impact on the clearance of M8 but not on that of nelfinavir. The apparent clearance of M8 was 3.23 L/h it decreased to 1.87 L/h when nelfinavir was coadministered with ritonavir. After univariate selection, a large number of covariates were included in the full model. According to the acceptance criteria, none of the effect on clearance of nelfinavir on... 

Banfield CEi, u G-RR, Jen IF, Jensen PK, Schumaker RC, Perhach JL Affrime MB, Glue P. The effect of age on the apparent clearance of felbamate a retrospective analysis using nonlinear mixed-effects modeling. Ther Drug Monit (1996) 18,19-29. 

The AUCs of oxcarbazepine and its active metabolite (monohydroxyoxcarbazepine) were reduced by phenobarbital, by 43% and 25%, respectively. There were no other significant effects on the pharmacokinetics of oxcarbazepine. Another study found that phenytoin caused a 29% reduction in the AUC of monohydroxyoxcarbazepine. Another study found that the serum levels of monohydroxyoxcarbazepine were not affected by phenobarbital or phenytoin but its further conversion to dihydroxyoxcarbazepine was increased. Since the conversion to dihydroxyoxcarbazepine is a minor step in the metabolism of monohydroxyoxcarbazepine, the overall antiepileptic action of oxcarbazepine is unlikely to be altered. Correspondingly, a study found that phenytoin 100 to 375 mg daily increased the clearance of the active metabolite, monohydroxyoxcarbazepine by almost 40%." The AUC of monohydroxyoxcarbazepine was also 40% lower in the presence of carbamazepine. Similarly, carbamazepine, phenobarbitaL and phenytoin were found to increase the apparent clearance of monohydroxyoxcarbazepine by 31 to 35% in a study in children. ... 

In 12 healthy subjects the concurrent use of lomoxicam 4 mg twice daily for 14 days and digoxin 250 micrograms daily had only a small effect on the pharmacokinetics of each dmg. The apparent clearance of the digoxin was decreased by 14% while the maximum serum level of the lomoxicam was decreased by 21% and its elimination half-life increased by 36%. ... 

Kovarik JM, Hartmann S, Figueiredo J, Rouilly M, Port A, Rordorf C. Effect of rifampicin on apparent clearance of AnnPhaiTnaco er (2002) 36, 981-5. 

Absorption and distribution oral duloxetine is well absorbed with maximal plasma concentrations in 6 hours. Food delays the time to reach peak concentration from 6 to 10 hours and decreases 10% of absorption. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. 

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