Can Random Drug Concentrations Predict Adherence?

Adherence is critical for the success of HAART. Pharmacokinetics also plays an important role in the response to treatment of HIV infection. These two factors interact and can potentially affect virologic outcomes. A study presented by Liechty and colleagues explored the relationship between random measurements of antiretroviral drug concentrations and level of medication adherence [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 529]. In this prospective study, 88 HIV-infected patients had adherence measured by pill counts during three consecutive clinic visits. Nelfinavir, indinavir, efavirenz, and nevirapine plasma concentrations were randomly drawn within 1 month of the most recent adherence assessment. Adherence was dichotomized as above (high) or below (low) 90% based upon unannounced pill box counts. Drug levels designated as low were defined as trough concentrations more than one standard deviation below previously published means.

The authors found that, with the exception of indinavir, low random anti-retroviral plasma concentrations were highly associated with poor adherence (<90%). Normal range antiretroviral concentrations were associated with a wide range of medication adherence. The lesson learned from this study is that low random antiretroviral concentrations can indicate low adherence. However, normal or high random antiretroviral concentrations do not reliably assess adherence.

Drug-Drug Interactions

• Tenofovir and Didanosine: Tenofovir disoproxil fumarate (TDF) and didanosine (ddI) are FDA-approved for once-daily dosing. However, when given individually TDF must be taken in a fed state while ddI is given under fasting conditions. This was thought to limit the use of these two NRTIs in a once daily regimen. Because TDF is known to increase ddI exposure, some have hypothesized that the deleterious effects of food on ddI pharmacokinetics might be counteracted when this drug is co-administered with TDF under fed conditions. Kearney and colleagues evaluated the effect of concurrent and staggered administration of ddI and TDF on the fasted and fed pharmacokinetics of ddI [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 533]. In this study, 28 healthy volunteers went through 5 treatment phases:
  
  

  Period 1	ddI EC 400 mg (fasted) for one day
  Period 2	TDF 300 mg (fed) for 6 days
  Period 3	ddI EC 250 mg (fasted) plus TDF 300 mg (separated by 2 hours/fed) for one day
  Period 4	ddI EC 250 mg plus TDF 300 mg (concomitant/fed)
  Period 5	ddI EC 250 mg plus TDF 300 mg (concomitant/fasted)

  
  The authors found that when administered in a staggered fashion, a 250 mg dose of ddI EC + TDF resulted in an equivalent ddI AUC compared to 400 mg dosed alone (2.74 µg • hr/mL and 2.75 µg • hr/mL, respectively). Simultaneous administration of ddI EC 250 mg with TDF in the fasted and fed states resulted in a 14% increase and 11% decrease, respectively, in the ddI AUC.
  
  These results suggest that co-administration of TDF with a reduced dose of ddI under fed conditions did not significantly alter ddI pharmacokinetics. However, plasma TDF concentrations were not reported, and the potential clinical utility of combined TDF and ddI with food must be studied further.
  
  
• Tenofovir and Extended-Release Stavudine: Like TDF, extended release stavudine (d4T XR) is now FDA-approved for once-daily dosing. Since TDF increases ddI concentrations, investigators from Brystol-Myers Squibb evaluated whether the pharmacokinetics of TDF or d4T XR were affected by co-administration [Kaul, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 534]. Eighteen healthy volunteers received TDF and d4T XR alone, then combined as:
  
  

  Period 1	d4T XR 100 mg for one day
  Period 2	TDF 300 mg for 7 days
  Period 3	d4T XR 100 mg plus TDF 300 mg for one day

  
  TDF did not alter the AUC, Tmax, or Cmax of d4T XR (100 mg qd). Analysis is ongoing to determine the effect of d4T XR on TDF pharmacokinetics.
  
  
• Indinavir/Ritonavir and Rifampin: Current guidelines prohibit the concomitant use of indinavir (IDV) with the anti-tuberculous agent rifampin (RIF). IDV is a substrate and inhibitor of cytochrome P4503A4 (CYP3A4), while RIF is a potent inducer of that enzyme. Combination of these agents significantly reduces IDV plasma concentrations and can lead to treatment failure. Justesen and colleagues investigated whether the inducing effect of RIF could be overcome by ritonavir (RTV) (a potent CYP3A4 inhibitor) when administered in combination with IDV [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 542]. Six HIV-infected patients were treated with IDV/RTV 800/100 mg in combination with two nucleoside analogs and RIF 300 mg qd. The investigators observed an 87% decline in the IDV AUC12hr when co-administered with RIF, even when combined with RTV 100 mg bid. Though these findings clearly indicate that RIF should not be co-administered with IDV/RTV 800/100 mg bid, further studies are needed to evaluate whether higher doses of RTV (200 or 400 mg bid) would compensate for the inducing effect of RIF.
  
  
• LPV/r and Phenytoin: Some anti-seizure medications such as phenytoin (Dilantin, DPH) are potent CYP3A4 inducers and can potentially lower plasma concentrations of PIs. Co-administration of NFV with phenytoin resulted in a 30% reduction in the phenytoin AUC and a 20% reduction in the AUC of the major NFV metabolite, M8, but had no effect on the NFV AUC [Shelton, ICAAC 2000]. To date, no studies have investigated the effects of phenytoin on LPV/r pharmacokinetics. Bertz and colleagues reported the results of a healthy volunteer study designed to determine whether there is a pharmacokinetic drug interaction involving LPV/r and Phenytoin [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 535]. The study had two arms: in Arm A, 12 healthy volunteers were treated with LPV/r 400/100 mg bid for 10 days after which phenytoin was added for 11 days. Subjects assigned to Arm B were treated with phenytoin alone 300 mg qd for 10 days after which LPV/r was added for another 11 days. The investigators observed a two-way drug interaction wherein phenytoin decreased the LPV and RTV AUC12hr by 30% and 35%, respectively, and RTV decreased the phenytoin AUC24hr by 23%. These results illustrate the complexity of drug interactions involving substrates, inducers, and inhibitors of the CYP450 enzymes. In this case, phenytoin accelerated LPV clearance, apparently by inducing CYP3A4, while RTV accelerated phenytoin clearance, perhaps by inducing an enzyme known as CYP2C9 which is responsible for phenytoin metabolism. Clinicians should probably avoid co-administration of these two drugs until further studies can identify optimal dosing strategies.
  
  
• Drug Interactions Involving Enfuvirtide: ENF (T-20)is a peptide fusion inhibitor that must be given subcutaneously. Investigators from Thailand examined whether co-administration of ENF 90 mg SQ bid with either soft gel saquinavir/ritonavir (SQVsgc/r) 1000/100 mg bid, RTV 200 mg bid, or RIF 600 mg qd affected the steady-state pharmacokinetics of ENF in 12 HIV-infected patients [Boyd, et al. Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 541]. The AUC12hr, Cmax, and Ctrough of ENF were not affected by concomitant administration of RIF, SQVsgc/r, or RTV. These findings are not surprising, since ENF is not a known CYP450 substrate, inhibitor, or inducer, making this drug less vulnerable to clinically significant drug interactions.
  
  
• Nelfinavir and Lopinavir/Ritonavir: Like other PIs, NFV and lopinavir/ritonavir (LPV/r) are substrates, inhibitors and inducers of the CYP3A4 enzyme, and thus are prone to complex pharmacokinetic drug interactions. Bertz and colleagues evaluated the effects of co-administration of LPV/r 400/100 mg bid and NFV 1000 mg bid on the steady-state pharmacokinetic parameters of LPV/r, RTV, NFV, and the major NFV metabolite M8 in 14 healthy volunteers [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 536]. The authors found that the LPV Cmax, AUC12hr and Ctrough were decreased during NFV co-administration by 21%, 27% and 33%, respectively. Similar decreases in RTV concentrations were noted, while the AUC of M8 increased by 3-fold. The authors concluded that patients taking this PI combination would need to increase the LPV/r dose to prevent treatment failure. This interaction appears similar to the amprenavir interactions with LPV/r, although the reduction in the LPV/r concentrations is not as great. It may be best to avoid co-administration of these agents, and resort to other better studied PI combinations.
  

Making Nelfinavir a Better Drug?

NFV bioavailability is improved with a moderate fat meal, but it is unknown whether increased caloric and fat intake would further optimize NFV absorption and increase NFV concentrations. To address this issue, investigators from Agouron Pharmaceuticals conducted a healthy volunteer study to evaluate the impact of three different meal contents (125 kcal–20% fat, 500 kcal–20% fat, 1000 kcal–50% fat) on NFV bioavailability following a single 1250 mg dose [Bleiber, et al. Abstract 544]. Results showed that the NFV AUC12hr increased with higher caloric/fat intake and was four-fold higher in subjects who consumed meals containing 1000 kcal–50% fat when compared to fasting conditions.

Though NFV bioavailability substantially increased with higher caloric and fat intake, one has to wonder how practical it is to recommend that patients consume such large amounts of fat twice daily for long periods of time. These results reinforce the fact that NFV is a drug with suboptimal pharmacokinetic properties. While pharmacokinetics can be improved with an extraordinary (and unhealthy) diet, the real value of this study might be in promoting the search for a new formulation of NFV that would produce higher concentrations without the fat.

In a related study, Keiser and colleagues reported observational data on 162 women and 324 men, matched by baseline CD4 cell count and viral load, who were antiretroviral naïve and taking NFV containing regimens [Conf Retroviruses Opportunistic Infect. 2003 Feb 10-15;10th: Abstract No. 927]. The authors noted statistically significantly sex differences in time to treatment failure (295 days for women vs 236 days for men [P=0.016]), and percentage of patients achieving a viral load <400 c/mL at one year (48% for women vs 34% for men [P=0.009]) and two years (36% for women vs 25% for men [P=0.001]). Women on average weighed less than men (151 lbs vs 166 lbs, respectively). Increased baseline weight (>180 lbs) was the only independent risk factor for virologic and treatment failure. The authors concluded that in addition to body weight, other factors such as gender variation in protein binding and metabolism, or even biases associated with observational studies could had influenced their results. Nevertheless, these findings raise an important issue that should be confirmed in other large databases and prospective studies. Higher body weight could be associated with lower NFV concentrations, which could in turn predispose patients to resistance and treatment failure.

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