Expected poor absorption of chewed raltegravir in HIV patients with severe intestinal impairment
Cristina Gervasoni, Luigi Sacco University Hospital, Milan, Italy
22 April 2015
Sir,
Spinner and Coworkers have recently reported a case of an HIV-infected patient on raltegravir (RAL) maintenance therapy which required rifampicin for the treatment of disseminated Mycobacterium Avium infection [1]. By performing detailed RAL pharmacokinetic evaluations before and after adjusting RAL to the recommended dose of 800 mg BID the authors found comparable RAL AUC and Cmax values for 800 mg chewed vs. swallowed RAL, as well as for 400 mg chewed vs. swallowed RAL, thus providing conflicting results compared with our previous findings [2,3]. We believe, however, that these discrepancies are only apparent, being mainly biased by relevant confounding factors identified in this patient [1].
Firstly, the described patient suffered by very severe diarrhea (5 liters of watery diarrhea per day) and, most importantly, he had lack of intestinal drug absorption (that was the main reason for the escalation in the dose of the antimicrobial chemotherapy and for the shift from oral rifabutin to parenteral rifampicin). Indeed, in our previous in vivo/in vitro study we have provided evidence that RAL tablets administered to patients by swallowing do not fully disintegrate in the stomach, leading to negligible drug release from the tablets for the entire duration of gastric residence. In order to release the active ingredients, tablets need to reach the duodenum, where RAL presumably can find an environment (neutral pH) that can facilitate its dissolution. Accordingly, it is, therefore, not surprisingly to see that a patient with diarrhea and severe intestinal impairment did not beneficiate from a shift from swallowing to chewing RAL, just because his drug absorption in the duodenum was lacking.
Secondly, the patient was chronically treated with pantoprazole at 40 mg once daily, which represents an additional confounding factor for the pH-altering properties of this drug that may have further altered the gastric absorption and the intestinal passage of RAL.
Thirdly, the case report by Spinner et al did not quote our study in healthy volunteers [4] which clearly confirmed, in subjects without confounding factors (like diarrhea, intestinal impairment and/or co-medications), that chewing RAL was associated with a highly significant increase in drug absorption (90% increase in the RAL AUC) and reduced pharmacokinetic variability (with a reduction in the inter-individual coefficient of variations for the main RAL pharmacokinetic parameters ranging from 20 to >100%).
In conclusion chewed RAL – by increased drug absorption and reduced pharmacokinetic variability – can be generally considered as a useful and feasible option for the management of RAL/rifampicin interactions. However, assuming that the improved pharmacokinetics of RAL by chewing is related to increased drug absorption in the duodenum, this strategy cannot be successfully applied in selected patients with severe intestinal impairment.
1. Spinner CD, Wille F, Schwerdtfeger C, Thies P, Tanase U, Von Figura G, Schmid RM, Heinz WJ, Klinker HH. Pharmacokinetics of chewed vs. swallowed raltegravir in a patient with AIDS and MAI infection: some new conflicting data. AIDS Res Ther. 2015;12:1. doi: 10.1186/s12981-014-0041-8.
2. Cattaneo D, Baldelli S, Cerea M, Landonio S, Meraviglia P, Simioni E, Cozzi V, Fucile S, Gazzaniga A, Clementi E, Galli M, Rizzardini G, Gervasoni C. Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing. Antimicrob Agents Chemother. 2012;56:6132-6136.
3. Gervasoni C, Riva A, Impagnatiello C, Galli M, Cattaneo D. Is chewed raltegravir an option to care for HIV-infected patients with active tuberculosis? Clin Infect Dis. 2013;57:480-481.
4. Cattaneo D, Cossu MV, Fucile S, Riva A, Baldelli S, Meraviglia P, Landonio S, Impagnatiello C, Resnati C, Galli M, Clementi E, Capetti A, Rizzardini G,Gervasoni C. Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers: a randomized, open-label, 2-period, single-dose, crossover phase 1 study. Ther Drug Monit. 2015;37:119-25.
Expected poor absorption of chewed raltegravir in HIV patients with severe intestinal impairment
22 April 2015
Sir,
Spinner and Coworkers have recently reported a case of an HIV-infected patient on raltegravir (RAL) maintenance therapy which required rifampicin for the treatment of disseminated Mycobacterium Avium infection [1]. By performing detailed RAL pharmacokinetic evaluations before and after adjusting RAL to the recommended dose of 800 mg BID the authors found comparable RAL AUC and Cmax values for 800 mg chewed vs. swallowed RAL, as well as for 400 mg chewed vs. swallowed RAL, thus providing conflicting results compared with our previous findings [2,3]. We believe, however, that these discrepancies are only apparent, being mainly biased by relevant confounding factors identified in this patient [1].
Firstly, the described patient suffered by very severe diarrhea (5 liters of watery diarrhea per day) and, most importantly, he had lack of intestinal drug absorption (that was the main reason for the escalation in the dose of the antimicrobial chemotherapy and for the shift from oral rifabutin to parenteral rifampicin). Indeed, in our previous in vivo/in vitro study we have provided evidence that RAL tablets administered to patients by swallowing do not fully disintegrate in the stomach, leading to negligible drug release from the tablets for the entire duration of gastric residence. In order to release the active ingredients, tablets need to reach the duodenum, where RAL presumably can find an environment (neutral pH) that can facilitate its dissolution. Accordingly, it is, therefore, not surprisingly to see that a patient with diarrhea and severe intestinal impairment did not beneficiate from a shift from swallowing to chewing RAL, just because his drug absorption in the duodenum was lacking.
Secondly, the patient was chronically treated with pantoprazole at 40 mg once daily, which represents an additional confounding factor for the pH-altering properties of this drug that may have further altered the gastric absorption and the intestinal passage of RAL.
Thirdly, the case report by Spinner et al did not quote our study in healthy volunteers [4] which clearly confirmed, in subjects without confounding factors (like diarrhea, intestinal impairment and/or co-medications), that chewing RAL was associated with a highly significant increase in drug absorption (90% increase in the RAL AUC) and reduced pharmacokinetic variability (with a reduction in the inter-individual coefficient of variations for the main RAL pharmacokinetic parameters ranging from 20 to >100%).
In conclusion chewed RAL – by increased drug absorption and reduced pharmacokinetic variability – can be generally considered as a useful and feasible option for the management of RAL/rifampicin interactions. However, assuming that the improved pharmacokinetics of RAL by chewing is related to increased drug absorption in the duodenum, this strategy cannot be successfully applied in selected patients with severe intestinal impairment.
Cristina Gervasoni, Dario Cattaneo, Giuliano Rizzardini
Luigi Sacco University Hospital, Milan, Italy
References
1. Spinner CD, Wille F, Schwerdtfeger C, Thies P, Tanase U, Von Figura G, Schmid RM, Heinz WJ, Klinker HH. Pharmacokinetics of chewed vs. swallowed raltegravir in a patient with AIDS and MAI infection: some new conflicting data. AIDS Res Ther. 2015;12:1. doi: 10.1186/s12981-014-0041-8.
2. Cattaneo D, Baldelli S, Cerea M, Landonio S, Meraviglia P, Simioni E, Cozzi V, Fucile S, Gazzaniga A, Clementi E, Galli M, Rizzardini G, Gervasoni C. Comparison of the in vivo pharmacokinetics and in vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by chewing. Antimicrob Agents Chemother. 2012;56:6132-6136.
3. Gervasoni C, Riva A, Impagnatiello C, Galli M, Cattaneo D. Is chewed raltegravir an option to care for HIV-infected patients with active tuberculosis? Clin Infect Dis. 2013;57:480-481.
4. Cattaneo D, Cossu MV, Fucile S, Riva A, Baldelli S, Meraviglia P, Landonio S, Impagnatiello C, Resnati C, Galli M, Clementi E, Capetti A, Rizzardini G,Gervasoni C. Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers: a randomized, open-label, 2-period, single-dose, crossover phase 1 study. Ther Drug Monit. 2015;37:119-25.
Competing interests
All authors declare no conflict of interest