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Effects of High-Dose Vitamin C on the Steady State Pharmacokinetics of the Protease Inhibitor Indinavir in Healthy Volunteers
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Reported by Jules Levin
I have discussed these study results with several HIV pharmacologists who have said they do not think that the vitamin C - IDV interaction is clinically significant for most people on IDV which is boosted by RTV. One PK expert said the following regarding the study. The question of variability between patients may be an issue to consider:
the possibility of an effect of high-dose Vitamin C on the PK of ritonavir/saquinavir combinations or lopinavir would be unlikely in the absence of more data. Large amounts of vitamin C (ascorbic acid) could effect the pH of the GI tract to a small extent, making it more acidic. This type of environment would not be expected to negatively impact dissolution of ritonavir, saquinavir or lopinavir. I am not aware of data suggesting that high-dose vitamin C induces P450-mediated metabolism in humans (studies cited below are in animals, not generally a good model for human CYP induction).
In the featured study, it appears that even the effects high doses of vitamin C on the disposition of indinavir are rather modest (<15% decrease in AUC). With large variability in indinavir trough concentrations and small sample size, in my opinion the extent of effect on IDV trough concentrations cannot be determined from the study.
ICAAC poster A-1610. Douglas Slain, Pharm D, BCPS, Jarrett Ansden, PharmD, Rashida Khakoo, MD, Melanie Fisher, MD, MSc, David Lalka, PhD, Gerry Hobbs, PhD. School of Pharmacy, School of Medicine, West Virginia University, Morgantown, WV
Patients with HIV frequently use alternative/complementary agents such as herbs and vitamins. Unfortunately, very little is known about the effect of such substances on the pharmacokinetics (PK) of protease inhibitors. The study authors said the most commonly used complementary agent reported by patients with HIV is Vitamin C, with high doses (>1 gram) being commonly employed. It has been reported that Vitamin C has modulatory effects on the P-450 enzymes. More specifically increased intake may induce p-450 isoenzymes, including CYP3A. These enzymes are responsible for metabolizing protease inhibitors. The specific aim of this study was to determine if concmitant use of high-dose Vitamin C (1 gram daily) significantly alters the PK of indinavir (IDV).
BACKGROUND
Protease inhibitors, such as IDV, are potent antiretroviral agents used in the treatment of HIV infection. Protease inhibitors exhibit a concentration-response relationship and maintenance of serum concentrations that suppress viral replication, and without causing human toxicity is critical. Many of the drugs known to interact with protease inhibitors do so by inhibiting or inducing the activity/quantity of the CYP3A4. The recommended daily allowance (RDA) for Vitamin C supplementation in humans ranges from 60mg to 90mg, but HIV+ patients often consume high doses (daily doses og 1000-3000mg). Proposed reasons for Vitamin C use by patients with HIV include enhancement of immune function, reduction of oxidative stress, and anti-HIV activity. Information regarding interactions between vitamin C and protease inhibitors is non-existent. Results from several animal model experiments have shown that vitalin C exerts a modulatory effect on P-450 enzyme systems. Many of these studies have reported a positive correlation between vitamin C supplementation and deficiency and in increase or decrease in P-450 activity, respectively. Guinea pig studies suggest that excessive doses of vitamin C can induce the P-450 enzyme/activity. It should be mentioned, that most of these animal studies were performed before the scientific community differentiated the different P-450 isoenzyme families. Two recent animal studies have reported a relationship with CYP3A enzymes. The purpose of thios study was to determine if the daily administration of high-dose vitamin C (1000 mg daily) significantly alters the pharmacokinetics of IDV.
Seven healthy volunteers (6 male, 1 female) between the ages of 18-55 were enrolled. All subjects had to be within 30% of their ideal body weight. The subjects had to have normal serum chemistries, hematology, lipids, hepatic function tests, BUN, serum creatinine, glucose, and urinalysis including a drug screen for illicit substances. Patients were excluded if they had a history of diabetes, renal disease, nephrlithiasis, chronic GI diseases, blood dyscrasias or if taking substances or medications known to significantly induce or inhibit CYP3A4 or p-glycoprotein activity.
The study is prospective, open-label, and longitudinal. Plasma samples were collected from subjects for determining IDV levels at pre-dose ( 0 hr), 0.5, 1, 2, 3, 4, and 5 hours after 4 steady state doses of IDV 800 mg eight hours apart. After a 7-day washout period, subjects were started on 1000 mg of vitain C for 7 days. The subjects were also restarted on IDV 800mg every 8 hours beginning on the 6th day of vitamin C administration. After 4 doses of IDV, plasma was collected again to determine the IDV PK. Vitamin C and IDV were administered at least 3 hours apart.
All subjects were placed on a vitamin C content-controlled diet to calculate vitamin C content in food and drink throughout the study.
RESULTS
The mean steady state IDV Cmax concentration was significantly reduced (20%) when comparing with & without vitamin C after 7 days of vitamin C administration (10.3 ± 1.5 vs 8.2 ± 2.9 ug/ml, p=0.04).
The mean steady-state AUC 0-8 hrs of IDV significantly decreased (14%) after 7 days of vitamin C administration (26.4 ± 7.2 vs 22.7 ± 8.1 (ug.h/ml, p=0.009).
While not statistically significant, the IDV Cmin was 32% lower with vitamin C (0.27 ± 0.17 vs 0.18 ± 0.80, ug/ml p=0.09.
IDV oral clearance (0.44 ± 0.05 vs 0.53 ± 0.11 L/kg/h, p=0.06) and t 1/2 (1.02 ± 0.1 hrs, p=0.12) were not found to be significantly different.
The authors comments
The reduction in IDV Cmax and AUC after a week of vitamin C was striking. The difference in mean troughs were not statistically different, although the troughs were lower after vitamin C administration. A larger sample size may have detected a difference. The effect of the interaction was quite profound in 5 of the 7 subjects. One of the other volunteers not showing a difference in IDV concentration was a female, which raises the question of a gender effect. Slight changes in CYP3A4 activity have been reported to fluctuate with menstrual cycle phases. However, hormonal fluctuations within the menstrual cycle have not caused significant changes in CYP3A4 metabolism in previous studies.
In light of this, our findings would suggest that high doses of vitamin C could lead to a reductiob of PI effectiveness. It is possible that the degree of interaction between IDV and vitamin C could be more profound with even larger doses of vitamin C (eg, 3000 mg) or longer courses of vitamin C. Maximum induction of P-450 enzymes may not be seen until 10 days or more. Vitamin C appears to have some relationship with P-450 enzymes, including CYP3A. P-glycoprotein is a substance that appears to have a related role to CYP3A4 in the disposition of certain drugs, including protease inhibitors. The relationship between vitamin c and p-glycoprotein has not been well studied. A recent in vitro study reported that vitamin C might inhibit p-glycoprotein activity. This could mean that vitamin C could actually cause an increase in IDV bioavailability by that mechanism. At the present time it is difficult to separate the contributions of each of these mechanisms. Future studies are needed to identify the exact mechanism of interaction.
Clinicians must consider patient use and interactiob of alternative and complementary therapy.
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