Pharmacokinetic-pharmacodynamic relationships

Mathot RAA, van Schaick EA, Langemeijer MWE, Soudijn W, Breimer DD, Ijzerman AP, Danhof M. Pharmacokinetic-pharmacodynamic relationship of the cardiovascular effects of the adenosine A receptor agonist A -cyclopentyladenosine (CPA) in the rat. J Pharmacol Exp Ther 1994 268 616-624. 

Avramis, V. and Panosyan, E. 2005. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations - the past, the present and recommendations for the future. Clinical Pharmacokinetics 44(4), 367-393. 

It has become increasingly accepted that the pharmacokinetic behavior of new drugs represents an important attribute, along with efficacy and safety. The frequency with which a drug must be taken is a function of several factors the half-life, the span between minimally efficacious concentrations and concentrations that cause side-effects, and the pharmacokinetic-pharmacodynamic relationship. Typically medicinal chemists optimize the predicted pharmacokinetics of... 

C(t) modeled according to two-compartment model with zero-order and first-order absorption Pharmacokinetic/pharmacodynamic relationship modeled using Hill model with first-order absorption. Modeled parameters matched experimental parameters when bicompartmental model with zero-order input was used. Linear PKs, anticlockwise hysteresis loop established for all doses studied. Apomorphine and growth hormone concentration predicted with good accuracy... 

Karlsson, M.O., Molnar, V., Bergh, J., Freijs, A., and Larsson, R., A general model for time-dissociated pharmacokinetic-pharmacodynamic relationships exemplified by paclitaxel myelo-suppression, Clin. Pharmacol. Ther., 63,11-25,1998. 

Hale MD, Nicholls AJ, Bullingham RES, Hene R, Hoitsma A, Squifflet J-P, Weimar W, Vanrenterghem Y, Van de Woude FJ, Verpooten GA. (1998) The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 64 672-683. 

Pharmacokinetic/Pharmacodynamic relationship - Steady-state levels of drug and anticoagulant effect are typically attained within 1 to 3 hours and are maintained until the infusion is discontinued or the dosage adjusted. 

Delbaldo, C., Chatelut, E., Re, M., Deroussent, A., Seronie-Vivien, S., Jambu, A., Berthaud, P., Le Cesne, A., Blay, J.-Y. and Vassal, G. (2006) Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clinical Cancer Research, 12, 6073-6078. 

Baumann, P. (1996) Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors. Clin Pharma-cokinet 31 444 69. 

J. P. Desager, Y. Horsmans (1995). Pharmacokinetic-pharmacodynamic relationships of Hl-anti-histamines. Clin. Pharmacokinet. 28 418. 

Kaiko, R.F., Benziger, D.P., Fitzmartin, R.D., Burke, B.E., Reder, R.F., Goldenheim, P.D. Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone, Clin. Pharmacol. Ther. 1996, 59, 52-61. 

Lewis, D., Cole, B. F., Wallace, P. K., Fisher, J. L., Waugh, N., Guyre, P. M., Fanger, M. W., Curnow, R. T., Kaufman, P. A., and Ernstoff, M. S. 2001. Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma A multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/wew. J. Immunol. Methods. 248 149-165. 

Fig. 4.10 Pharmacokinetic/pharmacodynamic relationship of ISIS 22023 in mouse liver following SC administration of a single 50 mg/kg dose to mice. Symbols represent observed concentrations or Fas mRNA levels (error bars represent standard deviation for ISIS 22023 concentrations, or standard error for Fas mRNA levels n = 3). Solid lines represent predicted ISIS 22023 concentrations or Fas mRNA levels using nonlinear regression.

Mendel DB et al (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9 327-337... 

The interpretation and assessment of the pharmacokinetics of protein biopharmaceuticals often pose additional challenges compared to small-molecule drug candidates, therefore requiring additional resources. In general, these biopharmaceutical drug candidates are subject to the same general principles of pharmacokinetics, but their similarity to endogenous molecules can cause considerable complications in the evaluation of pharmacokinetics and pharmacokinetic/pharmacodynamic relationships (Meibohm, 2006). 

Laurijssens BE, Greenblatt DJ. Pharmacokinetic-pharmacodynamic relationships for benzodiazepines. Clin Pharmacokinet 1996 30 52-76. 

VRLB is a semisynthetic derivative ofVLB (5 -noranhydrovinblastine), structurally distinguished from other members of its class by the modification of the cathar-anthine nucleus rather than the vindoline ring. This alteration is probably responsible for differences in its antitumor activity and tolerability profile compared with other vinca alkaloids [68]. VRLB is effective as monotherapy or in combination with a platinum derivative in patients with advanced NSCLC and advanced breast cancer [69,70]. Myelosuppression is the major dose-limiting toxicity. VRLB is administered weekly nadirs are usually reached within 14 days and patients recover within the next two weeks [71]. VRLB is also well absorbed orally. Oral and i.v. forms show similar interindividual variability, the same metabolism pattern, reproducible intrapatient blood exposure, and the same pharmacokinetic-pharmacodynamic relationship. Given at 60 mg/m /week for the first three administrations and then increased to 80 mg/m /week it achieved the same efficacy as i.v. VRLB (30 mg/m ) in terms of progression-free survival, overall survival, and objective response [70]. 

Desager JP, Horsmans Y Pharmacokinetic-pharmacodynamic relationships of Hj antihistamines. CUn Pharmacokinet 1995 5 419-432. 

Thus, the phenomenon of drug absorption is only one, albeit an important one, of several factors that determine a drug profile in the circulation. It is important to understand all of these factors before drug profiles, and in particular pharmacokinetic/pharmacodynamic relationships, can be fully characterized, particularly in a predictive sense. 

Bruno, R. Vivier, N. Veyrat-Follet, C. Monaty, G. Rhodes, G.R. Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationship for docetaxel. Invest. New Drugs 2001, 19 (2), 163-169. 

Sica DA, Gehr TW. Diuretic combinations in refractory oedema states pharmacokinetic-pharmacodynamic relationships. Clin Pharmacokinet 1996 30(3) 229-49. 

Karlsson MO, Molnar V, Bergh J, et al. A general model for time-dissociated pharmacokinetic-pharmacodynamic relationship exemplified by paclitaxel myelosuppres-sion. Clin Pharmacol Ther. 1998 63(l) ll-25. 

Mager DE. Quantitative structure-pharmacokinetic/pharmacodynamic relationships. Adv Drug Deliv Rev. 2006 58(12-13) 1326-1356. 

Mager, D.E. (2006) Quantitative structure-pharmacokinetic/ pharmacodynamic relationships. Advanced Drug Delivery Reviews, 58, 1326-1356. 

The pharmacokinetics/pharmacodynamics relationship, systemic and tissue levels of drug exposure, frequency of dosing following which the drug may demonstrate efficacy, and the strength of efficacy are very important factors that may affect further development of an NEC. They are all directly or indirectly related to drug delivery. 

PHARMACOKINETICS/ PHARMACODYNAMICS RELATIONSHIP BIOMARKERS AND PHARMACOGENOMICS, PK/PD MODELS FOR CONTINUOUS DATA, AND PK/PD MODELS FOR OUTCOMES DATA... 

Hoogerkamp A, Arends RHGP, Bomers AM, Mandema JW, Voskuyl RA, Danhof M. Pharmacokinetic/ pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect. J Pharmacol Exp Ther 1996 279(2) 803-812. 

Cha PCW, Duffy BJ, Walker JS. Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther 1992 51 334- 57. 

Danes R, Eogli S, Gennari A, et al. Pharmacokinetic— pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharma-... 

Gianni, L., Kearns, C.M., Giani, A., Capri, G., Yigano, L., Lacatelli, A., Bonadonna, G., and Egorin, M.J. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. Journal of Clinical Oncology 1995 13 180-190. 

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