CIPLADOC - AIDS updates

Ritonavir was approved in March 1996 by the US FDA for the treatment of patients with advanced AIDS, at a dose of 600 mg bid. Since then, it has been widely used as part of a triple drug regimen in combination with two nucleoside reverse transcriptase inhibitors. However, accumulating clinical experience with the drug brought to light its unfavourable side effect profile, which is dose dependent. During this period, the unfavourable pharmacokinetic profile of the protease inhibitor class of drugs also came under scrutiny.

As early as 1995, investigators had discovered that ritonavir was an extraordinarily potent inhibitor of the metabolism of other protease inhibitors. This is because it potently inhibits cytochrome P450 3A4, the enzyme system responsible for metabolism of the protease inhibitors. It was discovered that at lower doses (100-400 mg), ritonavir can inhibit the metabolism of a concurrently administered protease inhibitor, and result in increased bioavailability and half-life of the latter. This technique is referred to as “boosting”.

Today, the role of ritonavir in therapy is essentially as a protease inhibitor booster. This monograph discusses the role of ritonavir in boosted protease inhibitor regimens.

Although the HIV protease inhibitors have had a major clinical impact as a drug class, they have a relatively narrow therapeutic index. This is a result of generally unfavourable pharmacokinetic characteristics, adverse effects and the requirement for highly suppressive drug concentrations to prevent the emergence of resistance.

The concept of protease inhibitor (PI) boosting was developed to overcome these shortcomings. Most importantly, these regimens have been shown to produce profound and sustained control of viral replication, with attendant recovery of immune function.

After multiple doses of a drug are administered over several days of treatment, the maximum and minimum concentrations of drug achieved after each dose reach constant levels. This is referred to as the “steady state.” The six measures of pharmacokinetics generally used to describe the steady state are depicted in Table 1 and Figure 1.

Table 1: Key measures of pharmacokinetics

C max : C max is the peak or highest plasma concentration achieved during a dosing interval.

T max : T max is the time taken to reach the highest observed plasma concentration.

C min : C min is the lowest observed plasma concentration achieved during a dosing interval. C min is also called the ‘trough concentration', and generally occurs at the end of the dosing interval.

AUC (Area under the curve) : AUC is the total plasma exposure achieved during a certain time period. After repeated dosing, it is often expressed as the plasma exposure over a 24-hour period (AUC 0-24 ). AUC is derived from the area under the plasma concentration versus time curve (shaded area in Fig. 1).

T 1/2 (half-life) : This is the time taken for the plasma levels of drug to fall by 50%. Drugs with a short half-life are eliminated rapidly from the body, whereas those with a long half-life remain in the body for a longer period of time.

Bioavailability : This term refers to the amount of drug that reaches the systemic circulation.

The activity of PIs is dependent on the continuous maintenance of circulating concentrations that suppress viral maturation. Sustained, highly suppressive concentrations are critical for impeding the emergence of resistant variants, since HIV displays both a high mutation rate and rapid replication kinetics in vivo . Treatment regimens producing trough concentrations of inhibitor in plasma that allow persistent low-level viral replication therefore favour the accumulation of multiple mutations required for significant resistance. Thus, for PIs the C min and AUC are likely to correlate most closely with antiviral efficacy. The peak concentrations have also been found to correlate with toxicity of PIs.

The “therapeutic window” is the difference between the concentration of a drug that is minimally effective and that which is associated with unacceptable adverse events (Figure 2). Depending on the potency and toxicity of the drug, this window may be wide or narrow. The higher the C min above the inhibitory concentration, the higher the potential for viral suppression. The closer the C max to the upper limits of the therapeutic window, the more likely it is to be associated with adverse events. The duration for which the drug levels remain high may also be an important factor contributing to toxicity.

IC 50 / IC 90

This is the in vitro concentration of drug required to inhibit viral replication by 50%/90%.

There exists a range of IC (inhibitory concentration) values for any particular PI. IC 50 and IC 90 vary depending upon a number of factors, including the viral strain, cell type and assay used, and on adjustments made for plasma protein binding. Drug-resistant strains tend to have higher IC 50 values compared to wild type.

The C min /IC 50 ratio

The ratio of C min /IC 50 (inhibitory quotient or IQ) can provide a surrogate measure of a drug's ability to suppress HIV replication, by taking into account the relationship between plasma drug levels and viral susceptibility to the drug. Values several times greater than one would be desirable, as this would provide a degree of pharmacologic “forgiveness”, a characteristic which minimizes the impact of less than perfect adherence, an heterogenous viral population or variable drug absorption.

The utility of PIs is hampered by a high degree of interpatient variability in plasma exposure. The goal of PI boosting is to increase the exposure to these agents, ensuring sustained and effective concentrations throughout the dosing interval.

PI boosting is best achieved by administering ritonavir (usually low dose – ie, 100-400 mg once or twice daily) along with the PI.

Ritonavir may increase exposure of a concomitantly administered PI by its effect on the following processes:

Absorption
First-pass metabolism
Systemic clearance

General principles: Orally administered drugs dissolve in the stomach. In the small intestine, they are absorbed into the hepatic portal vein, and taken directly into the liver before entering the systemic circulation. A portion of the administered dose may be metabolized (first-pass metabolism) by the cytochrome enzymes CYP3A4 present in the intestinal wall and the liver. This determines the bioavailability of the drug. All protease inhibitors are primarily metabolized by CYP3A4 isoenzymes. 1

The bioavailability of a drug may be further reduced by efflux pumps such as P-glycoprotein (P-gp), which are present in the intestinal wall and serve to excrete any absorbed drug back into the intestinal lumen. Intestinal P-gp acts to limit the bioavailability of substrate drugs by pumping them from the enterocyte back into the gut lumen. In addition, the expression of P-gp at the level of the blood brain barrier has been shown to be a critical factor in preventing the entry of some drugs into the central nervous system. It has been shown that P-gp limits the oral bioavailability of indinavir, saquinavir and nelfinavir. 1

Once the drug reaches the systemic circulation, it is metabolized by the liver and removed from the circulation by renal clearance or secretion into bile.

Effects of ritonavir: The effects of ritonavir are depicted in Table 2 .

Table 2: Effects of ritonavir

Ritonavir exerts several effects, the net effect of which is to increase exposure of the second PI. These effects are as follows: .

Ritonavir inhibits P-glycoprotein transport in the intestine, which increases absorption of the second PI.

Ritonavir is one of the most powerful inhibitors of the metabolic enzyme CYP3A4 in the intestinal wall and liver, which reduces the extent of first-pass metabolism of the second PI.

Ritonavir inhibits metabolism by CYP3A4 in the liver, which reduces the rate of systemic clearance of the second PI.

Ritonavir can also improve penetration into various compartments of the body such as brain tissue, by inhibiting P-gp in the blood-brain barrier.

Figure 3 explains the abovementioned effects.

Thus, inhibition of P-glycoprotein and CYP3A4 can result in significantly higher C max values, or significantly longer half-lives. In this manner, ritonavir increases the C max of saquinavir and lopinavir, and increases the half-life of indinavir and amprenavir.

Improving the pharmacokinetic profile of these agents could result in benefits outlined in Table 3. 2

Table 3: Potential clinical advantages of ritonavir-boosted PI therapy
Pharmacokinetic effects	Clinical consequences
Increased bioavailability	Reduced dose and improved affordability
Decreased systemic clearance	Reduced dose and cost of therapy
Increased AUC	Increased antiretroviral activity
Increased trough (C min )	Less likelihood of resistance
Decreased peak (C max )	Reduced drug toxicity
Reduced pharmacokinetic variability	More predictable drug concentrations
Amelioration of food restrictions	Improves adherence

Ritonavir has a relatively poor tolerability profile. The toxicity of ritonavir is directly proportional to its plasma levels. Hence, the administration of lower doses of ritonavir diminishes the potential for various ritonavir-associated adverse effects, such as nausea, vomiting, oral paraesthesia, taste perversion and elevated lipid levels. The impact of ritonavir-boosting on the overall exposure to the concomitantly administered PI, and the subsequent tolerability profile of this regimen, should be examined individually for each ritonavir-PI pair.

Current therapy for HIV infection is directed toward the goal of total suppression of viral replication through the use of multiple agents. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the concept of PI boosting exploits the large increase in the plasma concentrations of other protease inhibitors when co-administered with ritonavir.