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"Therapeutic Drug Monitoring: Program in British Columbia"
Chris Alexander (biography)
English - 2002-04-15 - 30 minutes
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Summary :
The use of potent combination antiretroviral therapies has achieved a dramatic reduction in the morbidity and mortality associated with HIV-1 infection. However, up to 20% of therapy naīve patients fail to achieve virologic success in their 1st year on triple therapies with 20% more failing in the 2nd year. Variability in the response to antiretroviral agents has been attributed to virologic, immunologic, pharmacokinetic and behavioural differences between patients. The first two issues have been addressed with drug resistance testing and monitoring of patient CD4 cell counts as a standard of care. However, pharmacokinetic and behavioural problems are not routinely addressed by any objective measure. At the B.C. Centre for Excellence in HIV/AIDS we are exploring the utility of therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a tool for managing these issues.
While antiretroviral regimens are designed to maintain concentrations within the therapeutic window, the pharmacokinetic characteristics can vary significantly between individuals. Metabolic differences, disease state and drug-drug interactions are just a few of the factors that can lead to sub-therapeutic or toxic levels of antiretrovirals. Current efforts at the Centre are focused primarily on examining the drug-drug interactions involved in multiple drug rescue therapy (MDRT) regimens including 2 or more PIs and/or NNRTIs.
Kaletra is currently an important component of salvage therapies administered in B.C. The active constituent lopinavir (LPV) is a potent protease inhibitor that has been formulated with small doses of ritonavir (RTV) to take advantage of the well-known boosting properties of the latter compound. The pharmacokinetic interactions of Kaletra with other individual PIs or NNRTIs have been generally well characterised; however, little is known about the co-administration of 2 or more of these drugs. The NNRTIs nevirapine (NVP) and efavirenz (EFV) decrease plasma levels of LPV and increased LPV/RTV doses are recommended to overcome this interaction. The PI amprenavir (APV) also lowers plasma levels of LPV/RTV while saquinavir (SQV) has no effect. The interactions of NVP or EFV on the pharmacokinetics of co-administered LPV/RTV and SQV-SGC or LPV/RTV and APV will be discussed.
Current protocols at the Centre call for full pharmacokinetic profiles involving multiple blood draws taken over the entire dosing period (usually 12 hours). These assessments, considered to be the most informative, yield important variables of drug disposition including peak and trough concentrations (Cmin and Cmax respectively) and areas under the curve (AUC). However, such a costly invasive procedure is not a practical approach to monitoring the HIV-infected population at large and has been limited to individuals on MDRT regimens.
In an attempt to reach a larger population, we are currently attempting to determine if PI and/or NNRTI concentrations in plasma samples collected for viral load testing are predictive of outcomes. This approach is unorthodox in that the timing of the drug administration relative to the blood collection is not known. However, we hypothesise that the concentrations of drugs should fall within a predictable range and measurement of drug levels outside these limits might reflect pharmacokinetic and/or adherence problems. With this approach, we hope to design a relatively inexpensive, non-invasive (in that it requires no addition blood collection) screening procedure to identify patients that may be at risk of drug failure or toxicity. Early results suggest that a single plasma drug level measurement taken a median five weeks after initiating therapy was a predictor of long-term outcomes including death. Results from these preliminary studies will be discussed.
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