Abstract
Variability in the relationship between pharmacological effect intensity and drug concentration (pharmacodynamics) is pronounced, usually exceeding pharmacokinetic variability. Whereas interindividual differences are large, intra-individual differences are much smaller, unless the individual experiences certain pathophysiological changes such as deterioration of renal function or progression of a chronic disease (for example, Parkinson’s disease). Failure to appreciate the magnitude of interindividual variability in the pharmacodynamics of a drug can compromise fixed dose clinical trial outcomes, making the drug appear less effective or more toxic.
In the face of pharmacodynamic variability it becomes important to identify useful predictors (covariates) of pharmacodynamic individuality to facilitate individually optimised pharmacotherapy. This requires clinical trial designs that incorporate extensive patient profiling, well beyond the usual short list of demographics (such as age, gender, race, bodyweight and smoking habits). In searching for predictors, it is helpful to appreciate the factors that may account for interindividual differences in the relationship between pharmacological effect intensity and drug concentration in plasma or other appropriate fluid. They include receptor density and affinity, the formation and elimination kinetics of endogenous ligands (such as the enkephalins), postreceptor transduction processes, homeo-static responses and the kinetic characteristics of transporters involved in drug transfer between fluids of distribution and the biophase.
Correction of drug concentrations in plasma for protein binding, consideration of active and interactive metabolites, stereospecific assays and attention to drug distribution disequilibria are essential for successful identification of factors affecting pharmacodynamic variability. Pharmaceutical delivery systems (the ‘hardware’) must be combined with guidance for individualising drug dosage (the ’software’ or user’s manual) to provide for optimal and cost-effective pharmacotherapy.
Similar content being viewed by others
References
Knott C, Reynolds F. Therapeutic drug monitoring in pregnancy: rationale and current status. Clin Pharmacokinet. 1990; 19: 425–33.
Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modeling of pharmaco-kinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther. 1979; 25: 358–71.
Lemmens HJM, Dyck JB, Shafer SL, et al. Pharmacokineticpharmacodynamic modeling in drug development: application to the investigational opioid trefentanil. Clin Pharmacol Ther. 1994; 56: 261–71.
Tiseo PJ, Thaler HT, Lapin J, et al. Morphine-6-glucur-onide concentrations and opioid-related side effects: a survey in cancer patients. Pain. 1995; 61: 47–54.
Warfield CA, Kahn CH. Acute pain management: programs in US hospitals and experiences and attitudes among US adults. Anesthesiology. 1995; 83: 1090–4.
Breitbart W, Rosenfeld BD, Passik SD, et al. The undertreatment of pain in ambulatory AIDs patients. Pain. 1996; 65: 243–9.
Fiset P, Lemmens HLM, Egan TE, et al. Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam. Clin Pharmacol Ther. 1995; 58: 567–82.
Koopmans R, Oosterhuis B, Karemaker JM, et al. Pharmacokinetic pharmacodynamic modelling of oxprenolol in man using continuous non-invasive blood pressure monitoring. Eur J Clin Pharmacol. 1998; 34: 395–400.
Adam HK, Kay B, Douglas EJ. Blood disoprofol levels in anaesthetized patients. Anaesth. 1982; 37: 536–40.
Padrini R, Piovan D, Busa M, et al. Pharmacodynamic variability of flecainide assessed by QRS changes. Clin Pharmacol Ther. 1993; 53: 59–64.
Jonkers RE, Koopmans RP, Settels JJ, et al. Kinetic-dynamic modeling of β1-adrenoceptor mediated cardiovascular effects of xamoterol in healthy volunteers at rest. 3rd Symposium on Frontiers of Pharmacokinetics and Pharmacodynamics; 1990; Baltimore.
Alradi AO, Carruthers SG. Evaluation and application of the linear variable differential transformer technique for the assessment of human dorsal hand vein alpha-receptor activity. Clin Pharmacol Ther. 1985; 38: 495–502.
Wald JA, Salazar DE, Cheng H, et al. Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics. J Pharmacokinet Biopharm. 1991; 19: 521–36.
Levy G, Ebling WF, Forrest A. Concentration- or effect-controlled clinical trials with sparse data. Clin Pharmacol Ther. 1994; 56: 1–8.
Reid JL. Dose-plasma concentration-effect relationship of felodipine in essential hypertension: a review. J Cardiovasc Pharmacol 1990; 15 (4 Suppl.): S50–6.
Levy G. Variability in animal and human pharmacodynamic studies. In: Rowland M, Sheiner LB, Steimer J-L, editors. Variability in drug therapy: description, estimation, and control. New York: Raven Press, 1985: 125–38.
Mandema JW, Stanski DR. Population pharmacodynamic model for ketorolac analgesia. Clin Pharmacol Ther. 1996; 60: 619–35.
Lapka R, Sechser T, Rejholec V, et al. Pharmacokinetics and pharmacodynamics of conventional and controlled release formulations of metipranolol in man. Eur J Clin Pharmacol. 1990; 38: 243–7.
Pitsiu M, Parker EM, Aarons L, et al. Population pharmacokinetics and pharmacodynamics of warfarin in healthy young adults. Eur J Pharm Sci 1993 1: 151–7.
Egan TD, Minto CF, Hermann DJ, et al. Remifentanyl versus alfentanil. Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology. 1996; 84: 821–33.
Adkison KDK, Powers KM, Artru AA, et al. Effect of paraaminohippurate on the efflux of valproic acid from the central nervous system of the rabbit. Epilepsy Res. 1996; 23: 95–104.
Naora K, Ichikawa N, Nishimura N, et al. Saturable transport of valproic acid in rat choroid plexus in vitro. J Pharm Sci. 1996; 85: 423–6.
Nutt DJ, Woodward WR, Hammerstad JP. Pharmacokinetics of intravenous levodopa: implications for mechanisms of therapeutic actions of levodopa and carbidopa. In: Fahan S, et al., editors. Recent development in Parkinson’s disease. New York: Raven Press, 1986: 239–45.
Montgomery EB. Pharmacokinetics and pharmacodynamics of levodopa. Neurology. 1992; 42 Suppl. 1: 17–22.
Friedman A, Kaufer D, Shemer J, et al. Tur-Kaspa: pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat Med. 1996; 2: 1382–5.
Tamsen A, Sakurada T, Wahlström A, et al. Postoperative demand for analgesics in relation to individual levels of endorphins and substance P in cerebrospinal fluid. Pain. 1982; 13: 171–83.
Dundee JW, Richards RK. Effect of azotemia upon the action of intravenous barbiturate anesthesia. Anesthesiology. 1954; 15: 333–46.
Danhof M, Hisaoka M, Levy G. Kinetics of drug action in disease states. II: effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset of loss of righting reflex. J Pharmacol Exp Ther. 1984; 230: 627–31.
Hisaoka M, Levy G. Kinetics of drug action in disease states. XIII: effect of dialyzable component(s) of uremic blood on phenobarbital concentrations in rats at onset of loss of righting reflex. J Pharmacol Exp Ther. 1985; 234: 180–3.
Whitfield LR, Levy G. Relationship between concentration and anticoagulant effect of heparin in plasma of normal subjects: magnitude and predictability of interindividual differences. Clin Pharmacol Ther. 1980; 28: 509–615.
Whitfield LR, Schentag JJ, Levy G. Relationship between concentration and anticoagulant effect of heparin in plasma of hospitalized patients: magnitude and predictability of interindividual differences. Clin Pharmacol Ther. 1982; 32: 503–16.
Zhou H-H, Koshakji RP, Silberstein DJ, et al. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites. N Engl J Med. 1989; 320: 565–70.
Lew KH, Ludwig EA, Milad MA, et al. Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 1993; 54: 402–14.
Contin M, Riva R, Albani F, et al. Pharmacokinetic optimisation in the treatment of Parkinson’s disease. Clin Pharmacokinet. 1996; 30: 463–81.
Triggs EJ, Charles BG, Contin M, et al. Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients. Eur J Clin Pharmacol. 1996; 51: 59–68.
Levy G. The case for preclinical pharmacodynamics. In: Yacobi A, Shah VP, Skelly JP, et al., editors. Integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. New York: Plenum Press, 1993: 7–13.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Levy, G. Predicting Effective Drug Concentrations for Individual Patients. Clin Pharmacokinet 34, 323–333 (1998). https://doi.org/10.2165/00003088-199834040-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199834040-00005