Pharmacokinetics dosage considerations

Celecoxib is a selective COX-2 inhibitor—about 10-20 times more selective for COX-2 than for COX-1. Pharmacokinetic and dosage considerations are given in Table 36-1. 

Antiemetics can be administered either intravenously or orally in this situation, depending on patient characteristics such as ability to take oral medications, dosage form availability, and cost considerations.5,10 The intravenous and oral routes are equally effective. When used at equipotent doses, the 5-HT3 antagonists have similar efficacy in preventing acute CINV, despite pharmacokinetic and receptor binding affinity differences.5,10,36... 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

SY Choe, E Lipka, LX Yu, JR Crison, GL Amidon. Optimization of dosage form release parameters based on pharmacokinetic and gastrointestinal transit time considerations. Pharm Res 13 S292, 1996. 

The adjustment of dose and dosing regimen for children and the elderly needs a special consideration because of several differences as compared to an adult individual. The differences may be due to many factors which include changes in pharmacokinetic parameters, age, body weight, surface area, and genetic predisposition. The present chapter provides some basic explanation about their differences and the dosage calculations because of these differences. 

Patients 13 years of age and older- 0.3 mg IM or slow IV, every 6 hours, as needed. Repeat once (up to 0.3 mg) if required, 30 to 60 minutes after initial dosage, giving consideration to previous dose pharmacokinetics use thereafter only as needed. In high-risk patients (eg, elderly, debilitated, presence of respiratory disease) or in patients where other CNS depressants are present, such as in the immediate postoperative period, reduce dose by about 50%. Exercise extra caution with the IV route of administration, particularly with the initial dose. 

Kita et al. [154] have undertaken a study to help predict the optimal dosage of omeprazole for extensive metabolizers in the anti-H. pylori therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n = 4) and poor metabolizers (ft = 3), participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for 12 h after each dose of medication. After each dose was administered, the pharmacokinetic profiles of omeprazole and its two metabolites were significantly different between extensive metabolizers and poor metabolizers. The area under the plasma concentration-time curve of omeprazole in extensive metabolziers was disproportionally increased 3.2- or 19.2-fold with dose escalation from 20 to 40 to 80 mg omeprazole, respectively. In contrast, the area under the plasma concentration-time curve of omeprazole was proportionally increased with the higher dose in poor metabolizers. The area under the plasma concentration-time curve of omeprazole after 20 mg administration to poor metabolizers was almost equal to the area under the plasma concentration-time curve in extensive metabolizers after 80 mg administration. The recommended dose of omeprazole for extensive metabolizers is a maximum of 80 mg x 2/day based on pharmacokinetic considerations. 

Pharmacokinetics Tolcapone, taken orally, is readily absorbed, and its absorption is not influenced by food. It is extensively bound to plasma albumin (>99 percent), and has a small volume of distribution (0.13 L/kg). The plasma half-life is approximately two hours, although inhibition of COMT may last considerably longer due to its affinity for the enzyme. Tolcapone is extensively metabolized, and its metabolites are eliminated in both the urine and feces. Dosage may need to be adjusted in individuals with moderate or severe cirrhosis. 

Pharmacokinetic/Pharmaceutical Dosage Form/Pharmacodynamic Considerations in the Design of A Controlled Drug Delivery System... 

Reetze-Bonorden P, Bohler J, Keller E. Drug dosage in patients during continuous renal replacement therapy Pharmacokinetic and therapeutic considerations. Clin Pharmacokinet 1993 24 362-79. 

Jones TE. The use of other drugs to allow a lower dosage of cyclosporin to be used. Therapeutic and pharmacoeconomic considerations. Clin Pharmacokinet 1997 32(5) 357-67. 

---