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Maintaining adequate PI exposure is important for antiviral efficacy

For PIs, the Cmin and AUC are likely to correlate most closely with antiviral efficacy.6-8

  • When exposure to an effective antiviral drug is high, virus is most likely to be inhibited. As drug levels fall between dosing intervals, the inhibitory pressure on the virus decreases and may fall to a level that allows the virus to begin to replicate. Antiviral resistance is most likely to develop during periods of rapid viral replication
  • However, the best pharmacokinetic predictor of efficacy is not yet known, and it is possible that this may differ for different PIs and perhaps for different dosing regimens (e.g. once-daily or twice-daily administration)
  • There is an equilibrium between protein-bound drug, free drug in plasma and free drug in the cell (Figure 2). Intracellular exposure is likely to be a highly important factor contributing to antiviral activity since this is where much of the drug activity may occur. However, the extent to which intracellular exposure can predict efficacy is not yet known

Figure 2. Intracellular drug levels.

The extent of PI exposure may be related to toxicity

The difference between the concentration of a drug that is minimally effective and that which is associated with unacceptable adverse events is termed the �therapeutic window� (Figure 3) and this can be wide or narrow depending on the potency and toxicity of the drug.

  • The closer the Cmax to the upper limits of the therapeutic window, the more likely it is to be associated with adverse events7,9
  • The duration at which drug levels remain high may also be an important factor contributing to toxicity9

Figure 3. The therapeutic window.

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