False-positive cannabinoid screens in adult cystic fibrosis patients treated with lumacaftor/ivacaftor

Cystic fibrosis (CF) is caused by gene mutations resulting in defective cystic fibrosis transmembrane conductance regulator (CFTR) protein activity [[1]Bell S.C. De Boeck K. Amaral M.D. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls.Pharmacol Ther. 2015; 145: 19-34Crossref PubMed Scopus (123) Google Scholar]. CFTR modulators have been developed to improve CFTR protein function [[1]Bell S.C. De Boeck K. Amaral M.D. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls.Pharmacol Ther. 2015; 145: 19-34Crossref PubMed Scopus (123) Google Scholar]. The combination of ivacaftor (IVA) and lumacaftor (LUM) partially restores CFTR protein function of F508del, the most common CF mutation [[1]Bell S.C. De Boeck K. Amaral M.D. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls.Pharmacol Ther. 2015; 145: 19-34Crossref PubMed Scopus (123) Google Scholar]. At our adult CF center, all patients are tested via urine drug screens annually for appropriate medication counseling. Urine immunoassays are used because sampling is easy and noninvasive, and they provide inexpensive rapid results [[2]Moeller K.E. Lee K.C. Kissack J.C. Urine drug screening: Practical guide for clinicians.Mayo Clin Proc. 2008; 83: 66-76Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar]. However, screening immunoassays may yield false-positive results that require confirmatory testing [[3]Moeller K.E. Kissack J.C. Atayee R.S. Lee K.C. Clinical interpretation of urine drug tests: What clinicians need to know about urine drug screens.Mayo Clin Proc. 2017; 92: 774-796Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. We reviewed relevant patient information and histories after false-positive immunoassay cannabinoid screening results were suspected among patients with CF receiving LUM/IVA. This retrospective analysis was performed at a single medical center in adult patients with CF from January 18, 2016, to February 15, 2017. Demographic information, findings from any previous cannabinoid screens, concomitant medication use, and time from initiation of LUM/IVA to the immunoassay screen were collected for all patients receiving LUM/IVA (Table 1). All patient records were de-identified for this analysis. Additionally, concomitant proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole) and pain relievers (eg, nonsteroidal antiinflammatory drugs and acetaminophen) were recorded, as they have also been shown to result in false-positive findings for cannabinoids.Table 1Details of immunoassay and GC–MS results, previous screening results, and concomitant medications.Patient numberSexImmunoassay results before LUM/IVA initiationSelect concomitant medicationsTime from LUM/IVA initiation to immunoassay screen, daysResult of immunoassay screenResult of GC–MS confirmatory test1FNever positiveOmeprazole165PositiveNegative2FNever positivePantoprazole213PositiveNegative3MNever positiveNone106PositiveNegative4FNever positiveLansoprazole, ibuprofen242PositiveNegative5MNever positiveOmeprazole205PositiveNegative6FNever positiveIbuprofen211PositiveNegative7FNever positivePantoprazole429PositiveNegative8MNever positivePantoprazole165PositiveNegative9MNever positiveOmeprazole, ibuprofen211PositiveNegative10MNever positiveNone260PositiveNegative11MNever positivePantoprazole66PositiveNegative12MPositiveaPatient had a known history of cannabis use but was not using at the time of the most recent screen.Esomeprazole174PositiveNegative13MNever positivePantoprazole70PositiveNegative14MNever positivePantoprazole335PositiveNegative15MNever positiveOmeprazole, ibuprofen, acetaminophen529PositiveNegative16MNever positiveOmeprazole, ibuprofen469PositiveNegative17MNever positiveNone352PositiveNegative18MPositiveOmeprazole, esomeprazole, ibuprofen329PositivePositivebPatient admitted to current use of cannabis.19MNever positiveEsomeprazole541PositiveNegative20FNever positiveOmeprazole387PositiveNegative21MPositiveaPatient had a known history of cannabis use but was not using at the time of the most recent screen.Esomeprazole, ibuprofen469PositiveNegative22MNever positiveOmeprazole286PositiveNegativeGC–MS, gas chromatography–mass spectrometry; LUM/IVA, lumacaftor/ivacaftor.a Patient had a known history of cannabis use but was not using at the time of the most recent screen.b Patient admitted to current use of cannabis. Open table in a new tab GC–MS, gas chromatography–mass spectrometry; LUM/IVA, lumacaftor/ivacaftor. Urine specimens were tested by immunoassay for the presence of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates. This analysis evaluated immunoassay results that were performed before initiation and between >2 months and 1.5 years after initiation of LUM/IVA therapy. The presence of cannabinoids was tested using the Syva EMIT® II immunoassay system (Siemens, Washington, DC), which has a specificity of 96% and a sensitivity of 96.6% at a cutoff of 50 ng/mL [[4]Kissner D. LeFlore Y. Narayan S.B. Marigowda G. Dorn E. Simard C. False-positive tetrahydrocannabinol urine immunoassay screens in patients with cystic fibrosis receiving combination lumacaftor/ivacaftor.in: Poster presented at: American Thoracic Society international conference; May 19–24, 2017; Washington, DC. 2017Google Scholar]. The 50 ng/mL cutoff is the US federal workplace drug screening standard. Values above this threshold indicate a positive drug test for cannabinoids. All specimens that tested positive for cannabinoids by immunoassay were submitted for confirmatory gas chromatography–mass spectrometry (GC–MS) analysis. During the review period, all 22 patients (aged 23–48 years) receiving LUM/IVA tested positive for cannabinoids via immunoassay. Of these 22 patients, 19 had tested negative for cannabinoids on prior routine immunoassay screens, before initiation of LUM/IVA therapy, and did not report any cannabis use. Three patients were known to have used cannabis. The positive immunoassay screens were obtained 66 to 541 days after initiation of LUM/IVA therapy (Table 1). Of the 3 patients who had tested positive for cannabinoid use in the past, 2 were not using cannabis during LUM/IVA treatment. The third patient admitted to current cannabis use. Samples from all 22 patients were tested using GC–MS to confirm the results, 21 of which tested negative. During the review period, of the 21 patients who tested negative for cannabinoids on GC–MS, 86% (n = 18) were taking concomitant medications (select concomitant medications included in Table 1) with their prescribed LUM/IVA. All patients in this study who did not have a history of cannabis use had screened negative before initiation of LUM/IVA, which suggests that the false-positive results on urine immunoassay are not due to concomitant medication use. The primary finding from this retrospective review was that urine specimens from 21 of 22 patients taking LUM/IVA tested false-positive for cannabinoids by immunoassay. Based on the 96% specificity rate for the EMIT II immunoassay, the false-positive rate should only be 4%. Limitations of this analysis are that the results are reported from a single center using only one immunoassay testing method, and neither ivacaftor nor lumacaftor pure substance have been individually tested in the urine immunoassay. It is important that clinicians and patients be aware that false-positive cannabinoid results on urine immunoassay may occur in people taking LUM/IVA, as such results may have negative ramifications for patients in the context of home-, school-, or workplace-related drug screening and eligibility for organ transplantation [[4]Kissner D. LeFlore Y. Narayan S.B. Marigowda G. Dorn E. Simard C. False-positive tetrahydrocannabinol urine immunoassay screens in patients with cystic fibrosis receiving combination lumacaftor/ivacaftor.in: Poster presented at: American Thoracic Society international conference; May 19–24, 2017; Washington, DC. 2017Google Scholar]. Any positive result should undergo confirmatory testing by mass spectrometry. While not infallible, these tests are more sensitive, specific, and accurate than immunoassay screening tests and provide the most reliable test results [[2]Moeller K.E. Lee K.C. Kissack J.C. Urine drug screening: Practical guide for clinicians.Mayo Clin Proc. 2008; 83: 66-76Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar,[5]Standridge J.B. Adams S.M. Zotos A.P. Urine drug screening: a valuable office procedure.Am Fam Physician. 2010; 81: 635-640PubMed Google Scholar]. To our knowledge, this is the first publication to report that patients with CF who take LUM/IVA have tested false-positive for cannabinoids on a urine immunoassay screen. DK, YL, and SBN have no declarations of interest. GM, CS, and CLC are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. Editorial assistance was provided under the direction of the authors by Susan Schade-Bijur, PhD, CMPP, and Jennifer Rossi, MA, ELS, MedThink SciCom, and funded by Vertex Pharmaceuticals Incorporated. This work was supported by Vertex Pharmaceuticals Incorporated.