Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir

Krishna, Rajesh; East, Lilly; Larson, Patrick; Valiathan, Chandni; Butterfield, Kristin; Teng, Yang; Hernandez‐Illas, Martha

doi:10.1111/jphp.12632

Cited by 22 publications

(24 citation statements)

References 12 publications

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“…Integrase inhibitors form a complex with divalent cations at the level of the gastro intestinal tract thus reducing their absorption . Administration recommendations: BIC: two hours before or six hours after antacids; simultaneous with mineral supplements DTG: two hours before or six hours after antacids or mineral supplements EVG/c: separate by four hours from antacids or mineral supplements RAL: not recommended with aluminium‐ and magnesium‐containing antacids.…”

Section: Discussionmentioning

confidence: 99%

The challenge of HIV treatment in an era of polypharmacy

2020

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Introduction The availability of potent antiretroviral therapy has transformed HIV infection into a chronic disease such that people living with HIV (PLWH) have a near normal life expectancy. However, there are continuing challenges in managing HIV infection, particularly in older patients, who often experience age‐related comorbidities resulting in complex polypharmacy and an increased risk for drug‐drug interactions. Furthermore, age‐related physiological changes may affect the pharmacokinetics and pharmacodynamics of both antiretrovirals and comedications thereby predisposing elderly to adverse drug reactions. This review provides an overview of the therapeutic challenges when treating elderly PLWH (i.e. >65 years). Particular emphasis is placed on drug‐drug interactions and other common prescribing issues (i.e. inappropriate drug use, prescribing cascade, drug‐disease interaction) encountered in elderly PLWH. Discussion Prescribing issues are common in elderly PLWH due to the presence of age‐related comorbidities, organ dysfunction and physiological changes leading to a higher risk for drug‐drug interactions, drugs dosage errors and inappropriate drug use. Conclusions The high prevalence of prescribing issues in elderly PLWH highlights the need for ongoing education on prescribing principles and the optimal management of individual patients. The knowledge of adverse health outcomes associated with polypharmacy and inappropriate prescribing should ensure that there are interventions to prevent harm including medication reconciliation, medication review and medication prioritization according to the risks/benefits for each patient.

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Section: Discussionmentioning

confidence: 99%

The challenge of HIV treatment in an era of polypharmacy

2020

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“…1 Raltegravir plasma levels were increased with coadministration of atazanavir, but the increases were modest and not clinically meaningful. 8 In a recent publication, raltegravir did not alter the pharmacokinetics of citalopram and desmethylcitalopram, and citalopram also did not alter the pharmacokinetics of raltegravir to a clinically meaningful extent. 1 Efavirenz and TMC125 had a modest influence on the pharmacokinetic profile of raltegravir; there was evidence of a modest reduction in C 12 h (21% and 34% mean decrease, respectively), which was likely because of a slight induction of UGT1A1; these changes are not clinically meaningful.…”

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confidence: 93%

“…Coadministration of raltegravir 400 mg twice daily and magnesium-or aluminum-containing antacids is not recommended. 8 In a recent publication, raltegravir did not alter the pharmacokinetics of citalopram and desmethylcitalopram, and citalopram also did not alter the pharmacokinetics of raltegravir to a clinically meaningful extent. 9 Raltegravir has a long occupancy time on the viral integrase.…”

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confidence: 93%

Single‐ and Multiple‐Dose Pharmacokinetics of Once‐Daily Formulations of Raltegravir

Krishna

Rizk

Larson

et al. 2017

Clinical Pharm in Drug Dev

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A new once-daily formulation of raltegravir, an integrase strand transfer inhibitor indicated in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus-1 infection, is under development. Single-dose and steady-state pharmacokinetics of 1200 mg for 2 formulations of raltegravir were characterized in 2 open-label phase 1 studies in healthy male and female subjects aged 18 to 55 years. The new raltegravir 600-mg formulation had a higher relative bioavailability compared with the 400-mg tablets. Once absorbed, both 3 × 400-mg and 2 × 600-mg dosage forms of raltegravir exhibited similar systemic pharmacokinetics; in dictating bioavailability, differences were from increased absorption that was the result of improved in vivo disintegration/dissolution. Food had a smaller effect on the pharmacokinetics of raltegravir when given as 2 × 600-mg formulation (42% vs 73% decrease in AUC ). Steady state was generally reached in 2 days, with little to no accumulation with multiple-dose administration. Raltegravir 1200 mg was found to exhibit pharmacokinetic properties amenable for once-daily dosing and was generally well tolerated in healthy subjects after single and multiple doses. The new formulation improved the bioavailability of this Biopharmaceutics Classification System class II compound.

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“…There have also been reports of concomitant oral administration of Mg 2+ ‐containing antacids inhibiting the gastrointestinal absorption of RAL. [ 17,18 ] In addition, in relation to DTG and EVG, there have been reports that concomitant intake of foods or food supplements containing calcium and iron ions by healthy volunteers reduced the values of RAL C max and AUC. [ 19,20 ] However, there have been no previous reports of interaction between the integrase inhibitors and polycationic polymer preparations.…”

Section: Discussionmentioning

confidence: 99%

Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation

Enoki

Suzuki

Ito

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Raltegravir (RAL) that can form chelates with multivalent metal cations shows lateral interactions with multivalent metal cation and polycationic polymer. We investigated the interactions of RAL with multivalent metal cation preparations, Al(OH)3 and LaCO3, and polycationic polymer preparations, bixalomer (Bxl) and sevelamer (Svl). Methods Immediately before the oral administration of 40 mg/kg RAL, the rats were administered orally with the vehicle, Al(OH)3, LaCO3, Bxl, or Svl, and the time course of RAL serum concentration was followed. The in vitro binding affinity of RAL with multivalent metal cation and polycationic polymer was also evaluated using isothermal titration calorimetry (ITC). Results When Al(OH)3, LaCO3, Bxl, or Svl was concomitantly administered with RAL, the maximum concentration and area under the curve were significantly lower than those when RAL was administered alone. ITC showed the interaction of RAL with Al(OH)3 as an enthalpy‐driven reaction and its interactions with LaCO3 and Bxl as entropy–enthalpy mixed reactions. Conclusions The interaction of RAL with Al(OH)3, LaCO3, Bxl, or Svl can inhibit RAL absorption into the gastrointestinal tract, and thus, the multivalent metal cation and polycationic polymer are the modifying factors that can affect RAL pharmacokinetics.

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Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir

Abstract: Overall, the use of metal-cation antacids with 1200 mg QD raltegravir is not recommended.

Cited by 22 publications

References 12 publications

The challenge of HIV treatment in an era of polypharmacy

The challenge of HIV treatment in an era of polypharmacy

Single‐ and Multiple‐Dose Pharmacokinetics of Once‐Daily Formulations of Raltegravir

Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation

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