Drug therapy pharmacokinetic studies

Four HIV-infected children undergoing intense antiretroviral combination therapy were switched to regimens including amprenavir and efavirenz after the failure of other drugs (9). Pharmacokinetic studies suggested that combinations of these drugs can result in suboptimal concentrations of amprenavir. This was evident in two of the children taking amprenavir and efavirenz, in combination with two NRTIs, who had undetectable concentrations of amprenavir within 4 hours of administration. The addition of ritonavir to the combination restored the blood concentrations of amprenavir to those normally recorded (median 3500 ng/ml). The most probable reason for this effect is enhanced metabolism of amprenavir due to induction by efavirenz. 

David Taylor is Chief Pharmacist at the South London and Maudsley NHS Trust. Honorary Senior Lecturer at the Institute of Psychiatry and Foundation President of the College of Mental Health Pharmacists. His main areas of research are pharmacokinetics and prescribing practice in mental health. His team at the Maudsley is widely involved in systemic reviews and meta-analyses of psychotropic drug therapy. David is lead author of the Maudsley 2001 Prescribing Guidelines (Martin Dunitz, 2001) and co-editor of Case Studies in Psychopharmacology (Martin Dunitz, 1998). 

Fig. 5. Selection of candidate genes for selection in a either a study examining the role of pharmacogenomics in drug disposition and/or action or alternatively, use as a chnical tool to individualize drug therapy. Those genes prioritized for inclusion should he those shown to contribute markedly to drug pharmacokinetics and/or dynamics.

Steimer J, Mallet A, Mentre F (1985) Estimating interindividual pharmacokinetic variability. In Rowland M et aL (eds) Variability in Drug Therapy Description, Estimation and Control. Raven Press New York Tanigawara Y, Nomura H, Kagimoto N, Okumura K, Hori R (1995) Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases. Biol Pharm Bull 18(2) 315-320... 

In 2008, a Phase lib study of bevirimat in patients failing HIV therapy due to drug resistance was completed successfully. The results of this study demonstrated that patients who have virus with the most commonly occurring amino acids at positions 369, 370, or 371 on Gag are much more likely to respond to bevirimat treatment. In contrast, those patients whose virus has polymorphisms (variants) at these positions are less likely to respond to the drug. Furthermore, pharmacokinetic/pharmacodynamic modelling demonstrated that a trough plasma concentration of greater than 20 pg/mL bevirimat is required for a robust response. 

The pharmacokinetic principles applied in pediatric drug therapy are, in general, similar to those utilized for adults. Data obtained in adult studies, however, are not always applicable to rational therapy in infants or young children. The infant must be regarded as a distinct organism (not a small adult), and lack of appreciation of this fact can result in serious harm and potentially in death. 

When ill persons are offered money over and above expenses to enter a clinical trial of a new drug therapy, the possibility of coercion exists. The reasoning is that if the patient is poor, they might not be able to afford the therapy without entering the trial. Contrast this experience with renally impaired volunteers recruited for a pharmacokinetic study of an antibiotic. Renal failure is not the target of therapy. The subjects receive no therapeutic benefit from participating and are paid as volunteers. 

Among DNA-based drugs, only antisense DNA is currently analyzed by capillary electrophoresis. Antisense DNA therapy requires reliable and convenient methods for sequencing short single-stranded oligonucleotides. A method for phosphorothioate antisense DNA sequencing by capillary electrophoresis coupled to UV detection has been developed based on a modified chain-termination sequencing method.Capillary gel electrophoresis alone or in combination with HPLC is also used for pharmacokinetics study of antisense... 

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