Multiple oral doses

Hartmann, D., P. A. Thiirmann et al. (2004). Plasma kinetics of zeaxanthin and 3 -dehydro-lutein after multiple oral doses of synthetic zeaxanthin. Am. J. Clin. Nutr. 79(3) 410 -17. 

Fletcher et al. [123] used a sensitive and specific gas chromatography-mass spectrometry method for the assay of primaquine in plasma and urine for studying the plasma kinetics. Preliminary studies on the effects of single and multiple oral doses were carried out. In both cases, the drug was completely removed from plasma in 24 h. The concentration of primaquine in plasma usually reached a peak 1-2 h after oral administration. The plasma elimination half-life was about 4 h. 

Shue YK, Sears PS, Walsh RB, Lee C, Gorbach SL, Okumu F, Preston RA. (2008) Safety, tolerance and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother 52 1391-1395. 

Fig. 2.7 Plasma concentration profile for multiple oral dose administration.

Figure 8. Plasma disposition of sulfadimidine (SDM), its 6-methylhydroxy (CH2OH), 5-hydroxy (SOH) and N -acetyl (N ) metabolites in plasma of a laying-hen during and after cessation of multiple oral dosing of 100 mg SDM/kg/day during 5 days ...

Absorption/Distribution - Oral absorption is nearly complete. Peak plasma levels are attained at approximately 3 hours. The plasma half-life ranges from 12 to 27 hours after multiple oral doses. Steady-state levels are approached in 3 to 5 days once at steady-state, no accumulation occurs during chronic therapy. Plasma levels are approximately proportional to dose. In patients with congestive heart failure (CHF NYHA class III), the rate of flecainide elimination from plasma is moderately slower than for healthy subjects. Plasma protein binding is about 40% and is independent of plasma drug level over the range of 0.015 to about 3.4 mcg/mL. 

Oxycodone/Lorazepam/Ethanol Multiple oral doses of pregabalin were coadministered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with those drugs. 

Systemic absorption Clinically significant serum concentrations may occur in some patients who have taken multiple oral doses for active C. c//fif/c/7e-induced pseudomembranous colitis or who have inflammatory disorders of the intestinal mucosa the risk is greater with the presence of renal impairment. 

Distribution - The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses. Varying degrees of hepatic and renal insufficiency do not affect the protein... 

Absorption - After multiple oral doses of 750 mg 3 times/day or 1250 mg 2 times/day for 28 days (steady-state), peak plasma concentrations averaged 3 to 4 mg/mL, plasma concentrations prior to the morning dose were 1.4 to 2.2 mg/L, and prior to afternoon or evening dose were 0.7 to 1 mg/L. 

Absorption - Sirolimus is rapidly absorbed following oral administration, with a mean time-to-peak concentration of approximately 1 hour after a single dose in healthy subjects and approximately 2 hours after multiple oral doses in renal transplant recipients. The systemic bioavailability of sirolimus was estimated to be approximately 14%. 

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (18 years of age and older), the exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicated that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. 

Fig. 13. Plasma drug concentration vs. time curve after administrations of multiple oral doses at 8-hour intervals.

Average values for fed adult patients, following a multiple oral dosing Unchanged drug... 

J. Ekstrand, G. Alvan, L.O. Boreus, A. Norlin, Pharmacokinetics of fluoride in man after single and multiple oral doses, Eur. J. Clin. Pharmacol. 12 (1977) 311-317. 

Sldell, F.R., Groff, W.A., Ellin, R.I. 1969. Blood levels of oxime and symptoms in humans after single and multiple oral doses of 2-pyridine aldoxlme methochlorlde. J. Pharmaceut. Sci. 58 1093-1098. 

Kaul S, Shukla UA, Barbhaiya R. Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses. J Clin Pharmacol 1995 35 830-839. 

Yasui N, Kondo T, Furukori H, et al. Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology (Berl) 2000 150(2) 185-190. 

Lorenz D, Mennicke WH, Behrendt W. Elimination of silymarin by cholecys-tectomied patients. 2. Biliary elimination after multiple oral doses. Planta Med 1982 45 216-223. 

Gee T et al Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother 2001 45 1843. [PMID 11353635]... 

Mathews. J.M.. Troxler. P.S. Jeffcoat. A.R. (1990) Metabolism and distribution of bromodichloromethane in rats after single and multiple oral doses. J. Toxicol, environ. Health, 30, 15-22... 

Ammon, S., Hofmann, U., Griese, E. U., Gugeler, N., Mikus, G. Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing, Br. J. Clin. Pharmacol. 1999, 48, 317-22. 

Tan W, et al. (2010) Pharmacokinetics (PK) of PF-02341066. a dula ALK/MET inhibitor after multiple oral dose to advanced cancer patients. J Clin Oncol 28 (228 s) (supplement, abstract 2596)... 

However, multiple oral dosing is associated with disadvantages ... 

Pharmacokinetics, safety and tolerability of multiple oral doses of 25,50 and 75 or 100 mg XYZ1234 given once daily over 7 days as capsules in healthy men in an open-label study. 

Open label study with three treatment groups, with multiple oral doses of 25 mg (Treatment Group I) and 50 mg (Treatment Group II) once daily, immediately after intake of a standard breakfast in a parallel-group design. Safety information and bioanalytical data were reviewed to determine the dose for Treatment Group III (multiple oral doses of 75 or 100 mg XYZ1234). 

Treatment A Multiple oral doses of 25 mg XYZ1234 as capsules, given once daily immediately after intake of a standard breakfast for seven days. 

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