A prospective study on urine alkalization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate

Figures & data

Table 1 Urine alkalization regimens used at the University of Virginia Medical Center

Intravenous regimen	Oral regimen
Sodium bicarbonate 75–150 mEq/L IV continuous infusion at 175 mL/hr	Sodium bicarbonate 2,600 mg (four 650-mg tablets) PO 6 times daily scheduled at 0000–0600-0900-1300-1700-2100 Acetazolamide 250 mg PO Q6H scheduled at 0000-0600-1200-1800 0.45% sodium chloride IV continuous infusion at 175 mL/hr

Abbreviations: IV, intravenous; PO, oral.

Table 2 Baseline demographics for high-dose methotrexate encounters

Demographics	Intravenous alkalization (n=20)	Oral alkalization (n=28)	P-value
Age (years)	52±16.5	55±16.1	0.90
Weight (kg)	80±19.9	79.5±20.3	0.84
Female, n (%)	14 (70)	11 (39)	0.04
Baseline serum creatinine (mg/dL)	0.8	0.7	NA
Baseline CrCl (mL/min)	121.4±67.6	119.8±65.3	0.81
Baseline AST (U/L)	23±52.3	23±49.7	0.95
Baseline ALT (U/L)	26±85.3	25±80.7	0.91
Baseline total bilirubin (mg/dL)	0.4±0.3	0.45±0.3	0.99
Primary malignancy, n (%)			0.66
Non-Hodgkin’s lymphoma	8 (40)	13 (46)
CNS lymphoma	8 (40)	8 (29)
Acute lymphoblastic leukemia	4 (20)	7 (25)

Table 3 Patient encounters analyzed

Encounters for methotrexate	Intravenous alkalization (n=43)	Oral alkalization (n=83)
Methotrexate regimen, n (%)
Hyper-CVAD (1 g/m^2 over 24 hrs)	7 (16)	10 (12)
2.8 mg/m^2 over 2 hrs	3 (7)	0
3.5 mg/m^2 over 2 hrs	30 (70)	62 (75)
COG ALL0232 (5 g/m^2 over 24 hrs)	3 (7)	11 (13)

Note: All values are reported as median±standard deviation unless otherwise specified.

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; CrCl, creatinine clearance (Cockcroft–Gault equation); COG, Children’s Oncology Group.

Table 4 Safety outcomes of the intravenous and oral regimens used for urine alkalization in patients receiving high-dose methotrexate

Toxicity	Intravenous alkalization (n=43)	Oral alkalization (n=83)	P-value
Acute kidney injury, n (%)	4 (9.3)	12 (14.5)	0.41
Change in CrCl (mL/min)	−23.2	−20	0.45
Delayed methotrexate clearance, n (%)	16 (37.2)	22 (26.5)	0.21
Increase in AST (U/L)	59.3	50.6	0.64
Increase in ALT (U/L)	91.9	59.6	0.34
Increase in total bilirubin (mg/dL)	0.38	0.48	0.14

Note: Acute kidney injury defined according to Kidney Disease Improving Global Outcomes Practice Guidelines.

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; CrCl, creatinine clearance (Cockcroft–Gault equation).

Table 5 Secondary outcomes of the intravenous and oral regimens used for urine alkalization in patients receiving high-dose methotrexate

Parameter	IV alkalization (n=12)	Oral alkalization (n=54)	P-value
Time to Urine output goal (hours)	9.2±3.4	5.9±3.4	0.1
Time to Urine pH goal (hours)	4.8±1.8	4.8±2.2	0.4
Time to Methotrexate (hours)	8.0±2.6	7.9±3.0	0.6
Length of Stay (days)	3.1±0.9	3.8±5.6	0.3

Note: Preadmission encounters only included with all other encounters excluded. All values are reported as median±standard deviation.

Table 6 Overview of previously published alternative regimens to intravenous sodium bicarbonate for urine alkalization

Author	Regimen	Comparator arm	Outcomes	Adverse events
Shamash et al^Citation8	Acetazolamide 500 mg IV every 6 hrs for 48 h	No comparator	No delayed clearance	No significant AEs
Rouch et al^Citation7	Sodium bicarbonate: 650 mg tablet or sodium citrate 500 mg/ citric acid 334 mg/ 5 mL every 6 hrs	Parenteral sodium bicarbonate (50–150 mEq) physician preference	No difference in AKI or hepatic injury	Diarrhea P=0.002
Visage et al^Citation17	Sodium bicarbonate: 1950 mg/m^2 or Sodium citrate-citric acid oral solution: 22.5 mEq/m^2/dose every 6 hrs	No comparator	Delayed clearance seen in 2% of cases	GI side effects reported in 43%
Roy et al^Citation15	Sodium bicarbonate: 3250 mg PO every 12 hrs Acetazolamide 250 mg-500 mg PO or IV every 6 hrs PRN urine pH <7.5+ possible outpatient alkalinization	Intravenous sodium bicarbonate (150 mEq per 1000 mL) AND oral sodium bicarbonate at 3250 PO every 4 hrs PRN for urine pH <7.5	No difference in MTX clearance Increase in LOS P=0.23 No difference in toxicity (AKI, hepatoxicity, myelosuppression)	No difference in change in creatinine clearance
Alrabiah et al^Citation18	Sodium acetate IV	Parenteral sodium bicarbonate	No difference in LOS, time to pH >8, MTX clearance, or AKI	No adverse events identified

Abbreviations: MTX, methotrexate; PO, oral; IV, intravenous; LOS, length of stay; PRN, as needed; GI, gastrointestinal.

Table S1 Delayed methotrexate clearance definitions for each regimen. Cases failing to achieve a protocol-specific plasma concentration goal at any single time point were defined as having delayed clearance

MTX Regimen	Goal MTX plasma level by time point following start of HDMTX infusion
24 hrs	42 hrs	48 hrs	72 hrs
2.8–3.5 g/m^2 over 2 hrs	<10 µmol/L	Not applicable	<1 µmol/L	<0.1 µmol/L
Hyper-CVAD (1 g/m^2 over 24 hrs)	<20 µmol/L	Not applicable	<1 µmol/L	<0.1 µmol/L
COG AALL0232 (5 g/m^2 over 24 hrs)	<150 µmol/L	<10 µmol/L	<6 µmol/L	N/A

Abbreviations: MTX, methotrexate; COG, Children’s Oncology Group.

Table S2 Medication utilization analysis for the intravenous and oral regimens used for urine alkalization in patients receiving high-dose methotrexate

Regimen	IV sodium bicarboanate (50 mEq vial)	IV sodium acetate (100 mEq vial)	PO sodium bicarbonate (650 mg tablet)	PO acetazolamide (250 mg tablet)
Intravenous (number of vials or tablets)	25.77	0	0.23	0
Oral (number of vials or tablets)	1.64	0.07	90.75	13.80

Table S3 Cost analysis for the intravenous and oral regimens used for urine alkalization in patients receiving high-dose methotrexate

Cost Analysis (US$)	IV sodium bicarboanate (50 mEq vial)	IV sodium acetate (100 mEq vial)	PO sodium bicarbonate (650 mg tablet)	PO acetazolamide (250 mg tablet)	Total
Cost per vial or tablet ($)	11.00	10.00	0.01	2.77	NA
Total cost of IV regimen per encounter ($)	283.44	0	0	0	283.44
Total cost of PO regimen per encounter ($)	18.09	0.66	0.91	38.21	57.87

Note: Costs are expressed as Average Wholesale Price accessed from Medi-Span May 6, 2019.¹³

Shamash J, Earl H, Souhami R. Acetazolamide for alkalinisation of urine in patients receiving high-dose methotrexate. Cancer Chemother Pharmacol. 1991;28(2):150–151.2060085

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Rouch JA, Burton B, Dabb A, et al. Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate. J Oncol Pharm Pract. 2017;23(1):3–9. doi:10.1177/107815521561091426467268

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Visage R, Kaiser N, Williams M, Kim A. Oral methods of urinary alkalinization for high-dose methotrexate administration: alternatives to intravenous sodium bicarbonate during a critical drug shortage. J Pediatr Hematol Oncol. 2018. doi:10.1097/MPH.0000000000001348

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Alrabiah Z, Luter D, Proctor A, Bates JS. Substitution of sodium acetate for sodium bicarbonate for urine alkalinization in high-dose methotrexate therapy. Am J Health Syst Pharm. 2015;72(22):1932–1934. doi:10.2146/ajhp15040726541946

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Lexicomp Online. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc; Published 2019 Available from: http://online.lexi.com. Accessed 56, 2019.

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