Introduction

Emerging Issues: Co Administration of
Acid-Reducing Agents in PI Therapy:
An Expert Pharmacist’s Perspective
Andrew Luber, PharmD
Consultant, Division of Infectious Diseases
University of Pennsylvania
Philadelphia, PA
INTRODUCTION
absorption of a specific antiretroviral. This “catch-22,” if you will, is now becoming an suffer from acid-related conditions such as emerging issue faced by patients and their heartburn. In all likelihood, they will reach caregivers. As will be described shortly, the for an over-the-counter (OTC) antacid, a H2 high frequency of self-reported use of agents blocker (H2B) (e.g. ranitidine), or a low- that affect gastric pH among HIV-infected patients underscores the need for increased omeprazole). At some point, these patients patient education regarding the concomitant may also request a stronger, prescription product to alleviate their symptoms. The use of these prescribed medications makes it easy for the clinician to remember what their pharmacokinetic (PK) data available on this issue and identifies the need for further are, not all patients will think of disclosing investigation into this growing problem. their use of these medications with their SELF-REPORTED USE OF ACID-
REDUCING AGENTS
The widespread use of these acid-reducing Apoints to widespread use of pH-altering medications, including OTC antacids, H2Bs, Specifically, drug-drug interactions between receiving HAART.1 Each had access to the Internet and had previously participated in protease inhibitors (PIs). The gastric acidity an established chronic illness sufferers’ PHARMACOKINETIC
prospective, interactive survey and answered CONSIDERATIONS
questions about their use of antiretrovirals, the frequency of adverse events, and the use Gastric Acidity
of ARAs. In order to help patients properly currently taken, photos were displayed of all Creating a less acidic environment is in direct opposition to the needs of many PIs, heartburn (62%), gastroesophageal reflux optimal drug dissolution and absorption. agents and some PIs have the potential to conditions, more than half (56%) took OTC produce negative drug-drug interactions. medications exclusively. A high percentage Subtherapeutic plasma levels of PIs could prescription agents to control excess acid production. Only a small minority (5%) was Enhancement and Dose Adjustment
taking prescription drugs alone. During the frequently used as a PK enhancer to increase differences were observed in the frequency circumstances, the increases in PI plasma patients receiving protease inhibitor (PI)- concentrations observed may help overcome negative drug interactions. However, some It should be recognized that the population PIs rely quite heavily on gastric pH for dissolution prior to absorption. In these instances, boosting with low-dose RTV may clinicians across the country. In this study, not enhance PI plasma drug levels because participants were affluent, gay white males. providers at inner city clinics paint a far ReyatazR) experiences significant reductions in area under the concentration-time curve treatment at these clinics often rely on (AUC) and in trough plasma concentrations (Cmin) when given with antacids and proton given limited funds and state assistance for pump inhibitors. Various efforts aimed at these medications. In this setting, clinicians compensating for these changes, including are more likely to know what the patient is low dose RTV and the use of coca-cola (for negative drug interactions observed when ATV is given with these agents. Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective Factors Affecting PI Drug Absorption
lopinavir/ritonavir (LPV/r, KaletraR) which A number of critical factors will determine less susceptible to changes in gastric pH. the extent to which a PI is absorbed into the blood stream from the gut. While gastric Measuring Drug Levels
acidity is a key factor, the rate of gastric emptying, amount of blood flow to the site In the best situation, the drug interactions of absorption, the ionizability, solubility, and lipophilicity of the PI and the presence in a formal pharmacokinetic study in which or absence of food, among others, play key roles. These differences between PIs, as patients receiving the PI in the presence and well as interindividual gastric pH responses absence of the ARA. Unfortunately, many of these drug interaction studies are currently explain why clinical failures among patients lacking. As a result, a number of recent blood level from patients receiving PIs in combination with ARAs in clinical practice. As mentioned above, the ability of a PI to be ionization and lipophilicity. In general, in caution for a number of reasons: 1) wide order to be dissolved, weak bases need an interpatient variability exists among patients acidic environment and weak acids need a receiving the same PI. As a result, the level solubility of drugs that are weak bases will because of a negative drug interaction but be decreased in the presence of agents that increase intraluminal gastric pH (e.g. H2 blockers, PPIs).2 However, in order for the observed reflects the last few doses the patient has taken. If taken with the wrong food requirements or the patient did not take the last few doses at the appropriate time and in a basic environment, weak bases are intervals (or the sample is drawn late), the PI level could be “low.” In addition, the level could be “therapeutic” but the patient may An additional cause of decreased absorption not have taken the PI with ARAs in the last is the binding of divalent cations of antacids and sucralfate to PIs that are ionized thereby wide intra-patient variability in PI levels resulting in poorly absorbed complexes (also over time. This may reflect the real world nature of these agents when given in clinical practice. As a result, if possible, it is best to do a number of levels over a few different solubility and absorption of the various PIs days before making any clinical decision to is not fully understood. At one end of the ensure that the level is reproducible and 4) the level is only as good as the methodology which is formulated as a acidic salt and of the laboratory performing the test. As a result, it is critical for clinicians to select a Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective assurance/quality control measures are implemented. Table 1. PK Results for ATV/PPI
(omeprazole 40 mg) Interaction Study
INTERACTIONS BETWEEN ARAs
ATV/r 300/100 +
ATV/r 300/100
ATV/r 400/100
+ PPI 40 + 8 oz
+ PPI 40 QD
Atazanavir
I teraction studies with ATV and antacid REYATAZ (atazanavir sulfate, Bristol-Myers Squibb) Data on file. buffered didanosine showed a significant patients receiving ATV in 10 clinics in Los identified 50 patients and their medical pharmacokinetic data (Table 1) evaluating level. Ultimately, levels were obtained on omeprazole (previously released as a “Dear alone and then in combination with 40 mg of Among the 15 patients receiving PPIs, 6 had respectively, Two techniques used to try to compensate for altered ATV exposure levels minimum of 0.27 mcg/dL. Of note, 5 of the 6 in the PPI group and 2 of the 4 in the H2B 400 mg and giving 8 ounces of cola at the Proton pump inhibitors appeared to have a concomitant use of ATV (alone or boosted greater effect at lowering ATV trough levels below the minimum definition compared to Studies investigating drug-drug interactions should be presented in the near future. Until the results are in, clinicians are wise to be prudent when using ATV with H2Bs and to follow the recommendation contained in the package insert: Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective “Reduced plasma concentrations of ATV are Table 2. LPV trough concentration vs ARA
use (Median and interquartile range)
Nonusers
ARA Users
Bertz R. et al., HIV7, Glasgow, UK, Nov. 2004; #P279 These data suggest no significant interaction The idea for separating H2B and ATV by 12 partially explained by the non-ionizable recognized, however, that these data are down and may be sufficient enough to allow concentrations throughout the study and are not from formal crossover pharmacokinetic Lopinavir/Ritonavir
Fosamprenavir
Ford et al conducted a study to determine the effect of antacids and ranitidine on the plasma concentrations in patients with HIV single-dose PK of FPV.10 Fosamprenavir is infection who participated in a clinical trial the phosphate ester prodrug of APV. This was an open-label, randomized, three-way, tion with tenofovir DF/emtricitabine); this trial evaluated LPV trough concentrations at volunteers participated and were randomized various time points throughout the 48-week medication list collected at each study visit, Ranitidine was given 1 hour prior to FPV in the BID arm. No reductions in LPV trough order to maximize the gastric pH at the time concentrations were observed in patients period of absorption. Maalox TC was taken time points throughout the 48 week-study Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective delivered to the gut at the time FPV was validated when FPV concentrations are at steady state. Studies are currently underway with RTV (both BID and QD) with PPIs and should be available for presentation soon. ranitidine. No effect with either ARA was CONCLUSION
concentrations. Table 3 shows the plasma espite the data already obtained for the considerable gaps in our knowledge when it Several studies currently underway will build upon this existing information and Table 3. Plasma APV PK Parameter
further elucidate the factors responsible for Treatment Comparisons
these phenomena. Such studies will also either confirm present cautionary Geometric Least Squares Mean Ratio (90% CI)
recommendations or lessen the seriousness Comparison
of this issue. Future insights will depend (µg*h/mL)
(µg/mL)
(µg/mL)
heavily on well-designed pharmacokinetic treatment comparison expressed as LSM ratio (90% CI) Ford SL et al. Antimicrob Agents Chemother. 2005;49(1):467-9.
Clinicians interested in conducting their own adjustment or dose separation. The small obtain usable results (Table 4). A patient gastric acid changes observed with antacids revert quickly. Such changes, coupled with this testing; in some cases, a letter from the the chelation effect of antacids, appear not to In the case of FPV and ranitidine, the AUC Table 4. Recommendations for
Therapeutic Drug Monitoring
negative interaction was observed, it needs • Obtain samples collected on more than one day to confirm • Time collection visit prior to next dose for trough situation. When given with low dose RTV, • Prepare and ship sample according to lab’s instructions APV concentrations are increased roughly • Send sample to a reputable and experienced lab 6-fold as compared to unboosted FPV; as a • Be sure patient has not taken dose just prior to showing up result, a 30% reduction in APV exposures • Make certain patient is adherent and taking medications the correct way at the same time each day still results in levels well in excess of those observed with unboosted APV and are well above levels needed for wild-type virus. It should be recognized that these data come If feasible, trying to obtain more than one plasma trough level may help identify what Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective is going on with the patient prior to any medication used by HIV-infected patients that affect gastrointestinal (GI) acidity and potential for negative drug interactions with concomitant administration of both agents International Congress on Drug Therapy in obtaining trough PI concentrations before and after the initiation of the PPI would help interactions with agents used to treat acid- exposure levels. It is also critical for related diseases. Ailment Pharmacol Ther. clinicians to evaluate all potential causes of therapy; these include patient adherence, 3. Reynolds JC. The clinical importance of incorrect food requirements, negative drug- drug interactions with antiulcer therapy. J Clin Gastroenterol. 1990;12(Suppl. 2):S54- incorrect dosing intervals by the patient, among others. Finally, clinicians should only use laboratories that they know are 4. Kaul S, Olszyk C, Ji P, Xie J, Whigan D, assurance/control measures. One laboratory enteric coated capsules co-administered with instrumental in developing PI assays is the atazanavir or atazanavir/ritonavir. Program Laboratory at National Jewish Medical & Retroviruses and Opportunistic Infections, Clearly, both pharmacologists and clinicians need additional data from future studies to clarify many of these issues. Some of this new data will be released shortly. In the 6. Klein R and Struble K. Office of Special meantime, clinicians can benefit from an Issues. U.S. Food and Drug Administration. ongoing association with a pharmacologist who can serve as a reference point for future administration of atazanavir with proton- pump inhibitors and H2 receptor blockers. pharmacology world will find insight and perspective regarding these studies from a International Congress on Drug Therapy in clinician’s point of view. Further effort will continue to require this team approach as REFERENCES
Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective reducing agents on Lopinavir/ritonavir plasma concentrations in HIV-infected patients. Program and abstracts of the 7th International Congress on Drug Therapy in HIV Infection, Glasgow, Scotland; November 14-18, 2004. Poster P279. 10. Ford SL, Wire MB, Lou Y, Baker KL, Stein DS. Effect of antacids and ranitidine on the single-dose pharmacokinetics of fosamprenavir. Antimicrob Agents Chemother. 2005;49(1):467-9. Emerging Issues: Co Administration of Acid Reducing Agents in PI Therapy An Expert Pharmacist’s Perspective

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