Maximum Serum Concentration

Mean maximum observed cetuximab (Cmax) values after first cetuximab administration are displayed as a function of dose in Fig. 14.1. Serum concentrations of cetuximab typically reached maximum levels approximately 1-2 h following the end of the cetuximab infusion, independent of dose. Mean cetuximab Cmax values ranged from 8.7 to 283.8 gg/mL after single cetuximab doses of 20 to 500 mg/m2, respectively. A linear relationship (coefficient of correlation, r2 = 0.98) between cetuximab dose and mean Cmax value was observed, indicating that maximum serum concentrations following infusion are predictable for each dose used. 

Abbreviations Crmx maximum cetuximab serum concentration AUCo-ob area under the concentration-time curve extrapolated to infinity CL total body clearance Vss volume of distribution at steady state terminal elimination half-life SD standard deviation. 

358 14 Clinical Drug Development of Cetuximab, a Monoclonal Antibody 

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Maximum serum concentrations of scopolamine occurred 10 to 30 minutes after subcutaneous administration (Ebert et al. 1998). The elimination half-life is approximately 220 minutes. 

Pharmacokinetics After oral administration approximately 2.4% of a single 1 g oral dose is absorbed. Maximum serum concentrations appear after approximately 1 hour, and are low even after a single 1 g dose. Olsalazine has a very short serum half-life of approximately 0.9 hours and is greater than 99% bound to plasma proteins. Urinary recovery is less than 1%. Total oral olsalazine recovery ranges from 90% to 97%. 

Absorption/Distribution - Following single IM injections of 500 mg and 1 g, maximum serum concentrations occur at about 1 hour. 

Ofloxacin - Maximum serum concentrations are achieved 1 to 2 hours after an oral dose. Steady-state concentrations are achieved after 4 doses. Ofloxacin is widely distributed to body tissues and fluids. Elimination is mainly by renal excretion 4% to 8% is excreted in the feces. A longer plasma half-life of about 6.4 to 7.4 hours was observed in elderly subjects, compared with 4 to 5 hours for young subjects. Dosage adjustment is necessary for patients with impaired renal function (Ccr 50 mL/min or less). 

Absorption - The oral bioavailability of tenofovir in fasted patients is about 25%. Maximum serum concentrations (Cmax) re achieved in about 1 hour. 

Absorption/Disthbution - After administration of 25 mg of etanercept by a single subcutaneous injection to 25 patients with RA, a mean half-life of approximately 102 hours was observed with a clearance of approximately 160 mL/h. A maximum serum concentration (Cmax) of approximately 1.1 mcg/mL and time to C ax approximately 69 hours was observed in these patients. 

Pharmacokinetics A study of single IV infusions of 3 to 20 mg/kg in Crohn disease or RA patients showed a linear relationship between the dose and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. The median terminal half-life of infliximab ranged between 8 to 9.5 days. 

Zanamivir (2) is a potent competitive inhibitor of viral neuraminidase glycoprotein, which is essential in the infective cycle of both influenza A and B viruses. It inhibits a wide range of influenza A and B types in vitro as well as in vivo. The concentrations of inhibiting in vitro plaque formation of influenza A and B virus by 50% in Madin-Darby canine kidney (MDCK) cells were 0.004-0.014 p.mol/L in laboratory-passaged strains, and 0.002-16 p.mol/L in assays of clinical isolates. Due to its low bioavailability, it is delivered by inhalation via the Diskhaler , 10 mg twice daily, or intranasally 2-4 times daily for 5 days. After an intravenous dose of 1 -16 mg, the median elimination half-life was ti/2 = 7 h, the volume of distribution at steady state was Vdss = 16 L, and 90% of the dose was excreted unchanged in the urine. After intranasal and inhaled (dry powder) administration, maximum serum concentrations occurred within 2h and the terminal phase half-lives were 3.4 and 2.9 h, respectively. The bioavailabilities were 10 and 25%, respectively, and 20% after inhalation of zanamivir (2) by nebulizer. 

Etanercept is administered by subcutaneous injection. The maximum serum concentration is reached after approximately 72 hours. The half-life is approximately 115 hours. 

Pharmacokinetics Oral. Maximum serum concentrations attained within 3 hours. Protein binding-. 96%-99%. Metabolized in liver. Excreted in bile and urine. Half-life 18.3 hr. IM Rapidly absorbed. Undergoes rapid metabolism. Half-life Few min. Long-acting form Approximately 10 wk. Vaginal Gel Rate limited by absorption rather than by elimination. Protein binding-. 96%-99%. Undergoes both biliary and renal elimination. Half-life 5-20 hr. 

After intranasal administration maximum serum concentration are achieved within 10 to 45 minutes. It is 80% bound to plasma proteins. 

Pharmacokinetics The pharmacokinetic profile of alemtuzumab was studied in a rising-dose trial in non-Hodgkin s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Campath was administered once weekly for a maximum of 12 weeks. Following intravenous infusions over a range of doses, the maximum serum concentration (C ax) and the area under the curve (AUC) showed relative dose pro-... 

The effects of co-administration of oral diltiazem, a potent inhibitor of CYP3A, on the pharmacokinetics of lovastatin have been evaluated in a randomized study in 10 healthy volunteers (10). Lovastatin is oxidized by CYP3A to active metabolites. Diltiazem significantly increased the oral AUC and maximum serum concentration of lovastatin, but did not alter its half-life. The magnitude of the increase of plasma concentration of lovastatin suggested that caution is necessary when coadministering diltiazem and lovastatin. 

Fig. 14.1 Mean ( SD) maximum serum concentration (Cmax) for cetuximab versus dose across all studies.

Pharmacokinetics Etanercept is given subcutaneously twice a week. The time to maximum serum concentration after a single injection is about 72 hours. Its median half-life is 115 hours. Data on elimination is not available. 

Toxicity. Toxic effects may be produced by serum concentrations greater than 2 mmol/litre. Blood concentrations of about 5 mmol/litre or more are usually fatal, although in one instance of survival which occurred after the ingestion of 22.5 g of lithium carbonate, the maximum serum concentration was 8.2 mmol/ litre a fatality due to the acute ingestion of lithium carbonate in which the serum concentration was 2.43 mmol/litre on admission to hospital and 1.93 mmol/litre at the time of death has also been reported. 

Somnolence was reported in a 27-year-old subject following an overdose of opipramol a maximum serum concentration of 0.115 pg/ml was determined ethanol was also detected (O. L. Pedersen et ai, Eur. J. clin. Pharmac., 1982, 23, 513-521). 

Testosterone (T) Female Abdomen, forearm MDTS spray solution Pharmacokinetic parameters Average and maximum serum concentrations of free and total T were significantly higher after application to the forearm compared to the abdomen V... 

Atovaquone is a hydroxynaphthaquinone that is effective in the prevention and treatment of murine Pneumocystis jiroveci pneumonitis. It also has effects against Toxoplasma gondii and Plasmodium falciparum. Food increases its absorption. The maximum serum concentration is dose-dependent, but absorption is reduced at doses above 750 mg. The maximum concentration occurs after 4-6 hours, with a second peak 24-96 hours later, suggesting enterohepatic cycling. The half-life is 77 hours. 

Mefloquine is readily absorbed after oral administration absorption is influenced by the formulation and is more rapid from an aqueous solution. Maximum serum concentrations occur after 1-A hours. Absorption is reduced by diarrhea. The half-life varies considerably and has been variously reported to be 7-23 days, 15-30 days, and 8-18 days (SEDA-13, 808) (1), (SEDA-16,308) (2). Plasma protein binding is high. Sick patients have a prolonged... 

Several modified-release formulations are available. Maximum serum concentrations occur at 1-3 hours with most of the standard formulations and at up to 6 hours with modified-release formulations. In aminophyl-line, the most widely used theophylline derivative, theophylline is combined with ethylenediamine to enhance its solubility. Since ethylenediamine is therapeutically inert, all the effects of aminophyUine, except for allergic reactions, are considered to stem from the theophyUine component. 

Indinavir. When administered with a high fai diet, indinavir (Crixivan) achieves a maximum serum concentration of V< ul the administered dose. The drug is 60% bound in the plasma. It is extensively metabolized by CYP 3A4, and seven metabolites have been identified. Oral bioavail-abiiity is good, with a of 0.8 0.3 hour. The half-life of elimination is 1.8 hour, nnd the elimination products are delectable in feces and urine. Indinavir also causes dyslipide-mm. The available dosage forms are capsules of 200, 333, and dOO mg. 

Ajir et al. (1997) reported that Asians had higher maximum serum concentrations, larger AUCs, and lower clearance of both adina-zolam and its major active metabolite than did their Caucasian and African American counterparts. With oral administration, Asians also had higher maximum serum concentrations for both adina-zolam and its metabolite. These findings support the concept that Asian patients require smaller doses of adinazolam than do white patients to achieve similar levels of adinazolam and its metabolite. 

If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the gastrointestinal tract with no substantial loss by first pass metabolism. Maximum serum concentrations are attained 1-2 h after oral dosing but may not be achieved if vomiting or ileus are present In children, ciprofloxacin dosage should not exceed 1 g d ... 

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