Subtherapeutic Posaconazole Prophylaxis in a Gastric Bypass Patient Following Hematopoietic Stem Cell Transplantation

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Case Report

Subtherapeutic posaconazole prophylaxis in a gastric bypass patient following hematopoietic stem cell transplantation

Emily A. Highsmith, PharmD, BCCCP, Department of Pharmacy, University Purpose. A case of invasive fungal infections (IFIs) with subtherapeutic of Texas MD Anderson Cancer Center, Houston, TX, USA posaconazole prophylaxis in a gastric bypass patient following hemato-

poietic stem cell transplantation (HSCT) is reported. Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 Vi P. Doan, PharmD, BCOP, Department of Pharmacy, University of Texas MD Anderson Cancer Center, Summary. A 52-year-old malnourished male with a medical history of Houston, TX, USA Roux-en-Y gastric bypass for obesity developed acute myelogenous leu- Todd W. Canada, PharmD, BCNSP, kemia and underwent allogeneic HSCT approximately 17 months later. He BCCCP, FASHP, FTSHP, FASPEN, was admitted 1 month after HSCT for failure to thrive and initiated on par- Department of Pharmacy, University of Texas MD Anderson Cancer Center, enteral nutrition due to worsening diarrhea and suspected gastrointestinal Houston, TX, USA graft-versus-host disease (GI GVHD). During admission, the patient was continued on daily oral posaconazole for antifungal prophylaxis and was found to have subtherapeutic posaconazole and deficient vitamin levels, likely secondary to his gastrojejunostomy and increased gastric transit time. The oral posaconazole was altered to twice-daily dosing in an effort to increase serum drug levels and prevent IFIs.

Conclusion. Patients with a history of gastric bypass are at increased risk for malabsorption of oral posaconazole and nutrients, especially following HSCT with suspected GI GVHD.

Keywords: gastric bypass, hematopoietic stem cell transplantation, intestinal absorption, posaconazole

Am J Health-Syst Pharm. 2021;78:1282-1286

ariatric surgeries such as gastric patients require long-term immuno- Bbypass procedures are increas- suppression for prevention of graft- ingly common elective procedures. versus-host disease (GVHD), as well as In 2018, the American Society for prophylaxis for Pneumocystis jiroveci Metabolic and Bariatric Surgeries es- pneumonia, invasive fungal infections timated that 252,000 bariatric sur- (IFIs), and viral infections. geries were performed, representing a Previous literature has established 40% increase over a 5-year period.1 As perioperative management for bariatric obesity rates continue to rise, proced- procedures including nutritional man- ures such as Roux-en-Y gastric bypass agement, as well as evaluation of vita- (RYGB) or gastric sleeve will increase mins and serum trace element levels.3 in prevalence. Unfortunately, the published guidance Hematopoietic stem cell trans- for oral medication absorption fol- plantation (HSCT) is considered to lowing RYGB or ways to ameliorate de- be a curative therapy for a variety of creased absorption is scarce.4 malignancies, including leukemias, We describe a patient who was for- Address correspondence to Dr. Highsmith myelomas, and lymphomas. Over the merly obese before RYGB who devel- ([email protected]). past 6 decades, HSCT has dramatic- oped acute myelogenous leukemia and © American Society of Health-System ally increased in prevalence. In 2015, underwent HSCT with subtherapeutic Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals. over 21,000 transplantations were per- serum posaconazole levels during use of [email protected]. formed, and this number is expected to oral tablets and nutrient malabsorption DOI 10.1093/ajhp/zxab164 increase.2 Following allogeneic HSCT, with severe malnutrition.

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Case report DNA and negative for C. difficile toxin, KEY POINTS and the transplant team treated him A 52-year-old malnourished male • Patients with altered gastric with vancomycin 125 mg orally 4 times was hospitalized for significant gener- anatomy may be at risk for daily to suppress colonization and pre- alized weakness, fatigue, and failure to malabsorption of drugs and vent an active infection. The rest of the thrive. His medical history was signifi- nutrients. patient’s GI multiplex panel was nega- cant for positivity for hepatitis B core tive for pathogens. Because of profound • Patients with gastrointestinal antibody and obesity with a body mass thrombocytopenia (Table 1), high risk 2 graft vs host disease (GVHD) index of 53.3 kg/m , and he underwent for bleeding, and patient refusal, a or increased gastric transit RYGB in May 2018. Before RYGB, the feeding tube was not initially placed.

time are at increased risk for Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 patient reported his weight to be 165 kg Parenteral nutrition (PN) was initiated altered intestinal absorption. with a weight loss of approximately on hospital day 5 for failure to thrive 100 kg over the course of a year. He was • The use of therapeutic drug and suspected GI GVHD via endoscopy diagnosed with acute myelogenous leu- monitoring may help guide and sigmoidoscopy performed the kemia in April 2019, for which he under- clinicians to optimal dosing re- same day. The patient’s tissue biopsies went allogeneic HSCT with cells from a gimens in patients exhibiting were negative for GI GVHD with the matched sibling in October 2019. Before malabsorption or altered clear- transplant team empirically treating the initiation of the HSCT conditioning ance. patient with an 8-day course of tapering regimen and throughout his admission methylprednisolone administered in October 2019, he experienced min- IV. Repeat endoscopy and sigmoid- imal appetite and increased vomiting oscopy were performed in December and diarrhea and continued to lose 2019, and tissue biopsies were again weight. He was enrolled on a protocol negative for GI GVHD. PN was discon- where he received a myeloablative temporal wasting was evident. He continued 5 days after placement of an en- intensity conditioning regimen that tinued to receive posaconazole 300 mg teral feeding tube, and the patient was consisted of busulfan (area under the orally daily. started on continuous enteral feeding curve target of 6,000), fludarabine, His hospital course was significant due to chronic poor oral intake. aldesleukin, and natural killer cells on for a large volume (>1 L/day) of watery Given the suspicion of GI GVHD, day –8 before stem cell infusion. His diarrhea while receiving an oral diet, malabsorption with a history of RYGB, GVHD prophylaxis regimen included which was concerning given that this and risk for fungal infection with con- posttransplant administration of cyclo- can indicate gastrointestinal infec- comitant use of corticosteroids, serum phosphamide on days 3 and 4, followed tion or GVHD (GI GVHD). The patient posaconazole trough levels were by administration of tacrolimus starting tested positive for Clostridioides difficile obtained to assess oral absorption. on day 5. He received posaconazole 300 mg intravenously (IV) daily for 14 days as IFI prophylaxis per our Table 1. Select Laboratory Values on Readmission institution’s standard of care. The pa- Analyte Value Reference Rangea tient was partially engrafted 19 days following HSCT but remained an- White blood cell count, /μL 7,400 4,000-11,000 emic and thrombocytopenic (Table 1). Red blood cell count, ×106/μL 2.72 4.5-6 His posaconazole dose was switched Hemoglobin, g/dL 7.9 14-18 to 300 mg of the oral tablets (three 100-mg tablets) daily for 20 days fol- Hematocrit, % 23.1 40-54 lowing HSCT. His hospital course was Mean corpuscular volume, fL 85 82-98 complicated by Burkholderia cepacia Platelet count, ×103/μL 18 140-440 septicemia requiring admission to the intensive care unit and treatment with Blood urea nitrogen, mg/dL 48 6-23 subsequent discharge on post-HSCT Serum creatinine, mg/dL 1.01 0.67-1.17 day 28. Two days after discharge, the Alanine aminotransferase, U/L 14 ≤41 patient experienced significant gener- Aspartate aminotransferase, U/L 21 ≤40 alized weakness, fatigue, dizziness, and hypothermia accompanied by rigors Total bilirubin, mg/dL 0.5 <1.2 and was readmitted to the hospital. Albumin, g/dL 3.2 3.5-5.2 Upon readmission, the patient’s weight aReference values are institution specific. was 53 kg and significant muscle and

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The posaconazole assay measured absorbing all medications. We suspected Discussion total drug concentration as opposed absorption issues with other oral medica- to the concentration of available free tions, such as valacyclovir, letermovir, and Posaconazole is a second-generation drug. Figure 1 illustrates the patient’s entecavir, but were unable to measure triazole medication commonly used posaconazole trough levels, all of which serum levels of these agents. Fortunately, for prophylaxis and treatment of IFIs. were subtherapeutic (<700 ng/mL) the patient did not develop infections re- It is a potent cytochrome P-450 iso- on an oral tablet dosage, despite ini- lated to the organisms for which these zyme 3A4 (CYP3A4) inhibitor and tial intravenous dosing of 300 mg medications provide prophylaxis, which prolongs the QT interval, requiring daily followed by 300 mg orally daily may support adequate absorption des- careful monitoring when taken subse- (during his prior hospitalization). As pite the RYGB procedure. In addition quently to CYP3A4 substrates or other depicted in Figure 1, following multiple to receiving immunosuppression and QT interval–prolonging medications. Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 instances of subtherapeutic trough anti-infective agents, the patient re- Commercially available formulations levels, the patient was transitioned to mained on pantoprazole during the include an oral suspension, a delayed- a dosing strategy with posaconazole course of his admission. release tablet, and an intravenous for- 5 300 mg administered twice daily Before initiating PN, a variety of mulation. Posaconazole has widely without achieving a posaconazole nutrient levels were assessed (Table 4) varying oral bioavailability, ranging from level of >700 ng/mL (Table 2). He was with notable hyperhomocysteinemia 8% to 47%. Factors that may enhance also initiated on bridge therapy with and folate and free retinol (vitamin A) the bioavailability of posaconazole in- caspofungin that was intended to con- levels consistent with deficiencies from clude administration with a high-fat tinue until posaconazole levels were RYGB-related malabsorption and poor meal, low gastric pH, and absence of 6,7 therapeutic. The patient’s heart rate– oral intake. Surprisingly, not all nu- diarrhea or mucositis. Furthermore, corrected QT interval (QTc) was also trient levels were abnormal and vitamin posaconazole’s formulation impacts its bioavailability. The oral suspension closely monitored over the course of B12 levels were notably elevated, which treatment and was unaffected by the in- may be attributed to an oral vitamin has been shown to have significantly creased dose of posaconazole (Table 3). supplement the patient reported taking lower bioavailability when adminis- During this admission, the pa- before admission. We were unable to tered without food or in the setting of 8,9 tient remained on oral tacrolimus cap- obtain the constituents of the vitamin acid-reducing agents. In contrast, the sules for prevention of GVHD (Table 2) supplement because the patient did delayed-release tablet has better absorp- 9 without evidence of malabsorption, as not have it at the time of admission. tion in both fed and fasted conditions. his serum tacrolimus levels remained The patient was subsequently dis- Other risk factors for subtherapeutic therapeutic (desired goal of 7–12 ng/mL) charged to inpatient rehabilitation on posaconazole levels include diarrhea with only minor dosage adjustments. hospital day 39 and was discharged and concomitant use of a proton pump 10 Because the patient’s altered gastric from rehabilitation on hospital day 51. inhibitor. In a prior study in which 63% anatomy resulted in rapid gastric transit He unfortunately died 1 month after and 14% of patients received a proton pump inhibitor and histamine H re- and diarrhea on an oral diet, it is un- discharge due to severe malnutrition 2 likely that the patient was appropriately and multiple-system organ failure. ceptor antagonist, respectively, only 18%

Figure 1. Posaconazole level monitoring and dosing strategies. PO indicates orally; BID, twice daily.

700 300 mg PO daily 300 mg PO BID 600 547 525 500 444

400

300 261

200 121 95 100 63

0 234567891011121314151617181920212223242526

Posaconazole Trough (ng/mL) on Days Since Admission

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it is plausible that low serum albumin Table 2. Select Medications During Readmission levels may result in an increased frac- Time Interval Medication tion of unbound drug. Because only the unbound drug is able to undergo Day 1–discharge Entecavir 0.5 mg orally daily metabolism, previous case reports have Day 1–discharge Letermovir 480 mg orally daily hypothesized that hypoalbuminemia Day 1–discharge Valacyclovir 500 mg orally twice daily may result in enhanced drug clearance, which would be reflected in total drug Day 2–discharge Pantoprazole 40 mg orally twice daily concentrations. Until there is an assay Day 1–day 8 Posaconazole 300 mg orally daily to measure free drug, it is difficult to Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 Day 9–discharge Posaconazole 300 mg orally twice daily ascertain whether the concentration of unbound drug is able to provide suffi- Day 9–discharge Caspofungin 50 mg IV daily cient antifungal coverage to prevent Day 1–day 18 Tacrolimus 1 mg orally every morning; 0.5 mg orally every IFIs.12 evening Data from previous trials suggest that Day 19–day 26 Tacrolimus 1 mg orally twice daily posaconazole trough levels of >700 ng/ Day 26–discharge Tacrolimus 1 mg orally every morning; 0.5 mg orally every mL are adequate for IFI prophylaxis.8 evening Others have shown that 18% to 29% of

Abbreviation: IV, intravenously. patients receiving oral posaconazole do not achieve these levels but do not appear to develop breakthrough infections.11,13 Delayed-release tablets are the Table 3. QTc Values During Patient’s Hospital Stay preferred oral formulation, and patients showed an increase in median trough Day After Admission QT Interval, ms level from 750 ng/mL to 1,090 ng/mL Day 11 488 following a transition from the oral sus- 8 Day 12 428 pension to tablets. Previous studies have shown de- Day 19 407 creased posaconazole levels following RYGB. Increased gastric pH from a reduced number of acid-secreting Table 4. Nutrient Levels Before Initiation of Parenteral Nutrition parietal cells affects the solubility of posaconazole, while the restricted Analyte Value Reference Rangea gastric pouch and decreased gastric Folate, ng/mL <2b 4.8-24.4 residence time reduce medication absorption.13 One study measured area Homocysteine, mg/L 7.0b ≤2 under the curve before and after RYGB Vitamin B , pg/mL 3,740b 211-946 12 in healthy volunteers and found a 42% Methylmalonic acid, nmol/mL 0.17 ≤0.40 reduction in drug level following the procedure.13 When RYGB is paired with Free retinol (vitamin A), μg/dL 17.5b 32.5-78 diarrhea or damaged gastric mucosa, it Vitamin D (25-OH), ng/mL 41 30-100 is likely that drug levels are even further Ceruloplasmin, mg/dL 22.8 19-31 reduced. Copper, μg/dL 104 75-145 GI GVHD has been associ- ated with protein loss, diarrhea, and Zinc, μg/dL 91 66-110 malabsorption. Inflammatory processes Albumin, g/dL 3.2 3.5-5.2 resulting from myeloablative intensity C-reactive protein, mg/L 7.37 <1 conditioning regimens and alloreactive donor T cells result in damaged small aReference ranges are institution specific. bAbnormal result. intestine mucosa.14-16 Impaired mu- cosal absorption and increased gastric transit time may result in nutrient of patients concomitantly receiving Posaconazole is also highly pro- and drug malabsorption. We contacted posaconazole had a serum level below tein bound (up to 98%) and predom- the manufacturer of posaconazole for 700 ng/mL, despite the acid reduction.11 inantly binds to albumin. Given this, information regarding this patient’s

AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 14 | July 15, 2021 1285 Case Report SUBTHERAPEUTIC POSACONAZOLE AFTER GASTRIC BYPASS management; however, there have been 2. D’Souza A, Lee S, Zhu X, Pasquini M. 10. Tverdek FP, Heo ST, Aitken SL, no studies published on subtherapeutic Current use and trends in hematopoi- Granwehr B, Kontoyiannis DP. Real-life posaconazole levels in patients with etic cell transplantation in the United assessment of the safety and States. Biol Blood Marrow Transplant. effectiveness of the new tablet possible GI GVHD and a history of gas- 2017;23(9):1417-1421. and intravenous formulations of tric bypass (Kamien J, Merck, personal 3. Mechanick JI, Apovian C, Brethauer S, posaconazole in the prophylaxis of communication, November 15, 2019). et al. Clinical practice guidelines for invasive fungal infections via the perioperative nutrition, meta- analysis of 343 courses. Conclusion bolic, and nonsurgical support of Antimicrob Agents Chemother. patients undergoing bariatric pro- 2017;61(8):e00188-17. Patients with a history of RYGB are at cedures—2019 update: cosponsored 11. Lenczuk D, Zinke-Cerwenka W, an increased risk of malabsorption, and by American Association of Clinical Greinix H, et al. Antifungal prophylaxis Endocrinologists/American College of with posaconazole delayed-release Downloaded from https://academic.oup.com/ajhp/article/78/14/1282/6245082 by BINASSS user on 15 July 2021 their risk may increase with worsening Endocrinology, The Obesity Society, tablet and oral suspension in a real-life diarrhea, especially after HSCT. Medi American Society for Metabolic and setting: plasma levels, efficacy, and tol- cations such as posaconazole that exhibit Bariatric Surgery, Obesity Medicine erability. Antimicrob Agents Chemother. variable bioavailability may have altered Association, and American Society 2018;62(6):e02655-17. absorption as in the case presented of Anesthesiologists. Obesity (Silver 12. Maleki S, Corallo C, Coutsouvelis J, Spring). 2020;28(4):O1-O58. Singh J. Failure to achieve therapeutic here. In addition to malabsorption, 4. McLachlan LA, Chaar BB, Um IS. levels with high-dose posaconazole altered clearance may play a role in Pharmacokinetic changes post-bariatric tablets potentially due to enhanced subtherapeutic levels. Assessing trough surgery: a scoping review. Obes Rev. clearance. J Oncol Pharm Pract. drug levels and adjusting dosing strat- 2020;21(5):e12988. doi:10.1111/obr.12988 2018;24(1):63-66. egies are required in these unique patient 5. Noxafil (posaconazole). Package insert. 13. Gesquiere I, Hens B, Merck & Co Inc; 2018. Van der Schueren B, et al. Drug populations. 6. Lipp H. Clinical pharmacodynamics disposition before and after gas- and pharmacokinetics of the tric bypass: fenofibrate and Disclosures antifungal extended-spectrum triazole posaconazole. Br J Clin Pharmacol. posaconazole: an overview. Br J Clin 2016;82(5):1325-1332. The authors have declared no potential con- Pharmacol. 2011;70(4):471-480. 14. Zesier R, Blazar BR. Acute graft- flicts of interest. 7. Brocks DR, Ben-Eltriki M, Gabr RQ, versus-host disease—biologic process, Padwal RS. The effects of gastric by- prevention, and therapy. N Engl J Med. Previous affiliations pass surgery on drug absorption and 2017;377(22):2167-2179. At the time of writing, Dr. Highsmith was em- pharmacokinetics. Expert Opin Drug 15. Naymagon S, Naymagon L, ployed by Houston Methodist Hospital. Metab Toxicol. 2012;8(12):1505-1519. Wong SY, et al. Acute graft-versus- 8. Dekkers BGJ, Bakker M, van der Elst KCM, host disease of the gut: consider- References et al. Therapeutic drug monitoring of ations for the gastroenterologist. 1. American Society for Metabolic posaconazole: an update. Curr Fungal Nat Rev Gastroenterol Hepatol. and Bariatric Surgery. Estimate Infect Rep. 2016;10:51-61. 2017;14(12):711-726. of bariatric surgery numbers, 9. Wiederhold NP. Pharmacokinetics and 16. Tang LA, Marini BL, Benitez L, et al. 2011–2018. Accessed April 20, safety of posaconazole delayed-release Risk factors for subtherapeutic levels 2020. https://asmbs.org/resources/ tablets for invasive fungal infections. of posaconazole tablet. J Antimicrob estimate-of-bariatric-surgery-numbers Clin Pharmacol. 2015;8:1-8. Chemother. 2017:72(10):2902-2905.

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