Retrospective Data Analysis Reveals Unusual Metabolism Pattern of Ethanol in Pediatrics as Compared to Adult and Geriatric Populations.

BACKGROUND: About 95% of consumed ethanol is metabolized by oxidative pathways. Less than 1% is metabolized via nonoxidative pathways: glucuronidation, sulfation, and the formation of fatty acid esters of ethanol. In neonates, the glucuronidation pathway has been reported to be underdeveloped but matures with age. This work compared the test results of patients' random urine samples submitted to our facility for ethyl glucuronide (EtG) and ethyl sulfate (EtS) measurements across pediatric and adult populations. METHODS: Test results (n = 63 498) from urine samples tested for EtG and EtS by quantitative liquid chromatography-tandem mass spectrometry at our facility were utilized for this study. EtG and EtS concentrations were compared across the age partitions 0 to 17 years (pediatric), 18 to 80 years (adult), and 81 to 100 years (geriatric). Eight pediatric patients from a tertiary academic hospital contributed clinical context via abstracted clinical information. RESULTS: Across the individual age partitions, 60% to 65% of patients had both EtG and EtS present in urine. Approximately 5% to 10% of patients had only EtG, and 25% to 35% had neither metabolite present. The lowest percentages (<1.5%) had EtS present in the absence of EtG. Markedly, no pediatric patients had only EtS present; compared to the adult population, this was statistically significant (Fisher exact test, P = 0.025). CONCLUSIONS: From the data presented in this work, EtG is more prevalent relative to EtS in urine samples of patients assessed for ethanol exposure.

Biological Testing and Interpretation of Laboratory Results Associated with Detecting Newborns with Substance Exposure.

BACKGROUND: Substance use during pregnancy is common, as is biological testing that is intended to help identify prenatal exposures. However, there is no standardized requirement for biological testing with either maternal or newborn specimens, nor is there standardization related to when testing occurs, how frequently testing occurs, what specimen(s) to test, what substances to test for, or how to perform testing. CONTENT: We review common specimen types tested to detect maternal and newborn substance exposure with a focus on urine, meconium, and umbilical cord tissue. We also review common analytical methods used to perform testing, including immunoassay, and mass spectrometry platforms. Considerations regarding the utilization of testing relative to the purpose of testing, the drug analyte(s) of interest, the specific testing employed, and the interpretation of results are emphasized to help guide decisions about clinical utilization of testing. We also highlight specific examples of unexpected results that can be used to guide interpretation and appropriate next steps. SUMMARY: There are strengths and limitations associated with all approaches to detecting substance exposure in pregnant persons as well as biological testing to evaluate a newborn with possible substance exposure. Standardization is needed to better inform decisions surrounding evaluation of substance exposures in pregnant people and newborns. If biological sampling is pursued, testing options and results must be reviewed in clinical context, acknowledging that false-positive and -negative results can and do occur.

False-Negative Confirmatory Testing in Patients With Cannabinoid-Positive Urine Drug Screens.

This cross-sectional study discusses false-negative results associated with a change in the reporting threshold of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol.

Cannabis Exposure and Adverse Pregnancy Outcomes Related to Placental Function.

Importance: Cannabis use is increasing among reproductive-age individuals and the risks associated with cannabis exposure during pregnancy remain uncertain. Objective: To evaluate the association between maternal cannabis use and adverse pregnancy outcomes known to be related to placental function. Design, Setting, and Participants: Ancillary analysis of nulliparous individuals treated at 8 US medical centers with stored urine samples and abstracted pregnancy outcome data available. Participants in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort were recruited from 2010 through 2013; the drug assays and analyses for this ancillary project were completed from June 2020 through April 2023. Exposure: Cannabis exposure was ascertained by urine immunoassay for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol using frozen stored urine samples from study visits during the pregnancy gestational age windows of 6 weeks and 0 days to 13 weeks and 6 days (visit 1); 16 weeks and 0 days to 21 weeks and 6 days (visit 2); and 22 weeks and 0 days to 29 weeks and 6 days (visit 3). Positive results were confirmed with liquid chromatography tandem mass spectrometry. The timing of cannabis exposure was defined as only during the first trimester or ongoing exposure beyond the first trimester. Main Outcome and Measure: The dichotomous primary composite outcome included small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy ascertained by medical record abstraction by trained perinatal research staff with adjudication of outcomes by site investigators. Results: Of 10 038 participants, 9257 were eligible for this analysis. Of the 610 participants (6.6%) with cannabis use, 32.4% (n = 197) had cannabis exposure only during the first trimester and 67.6% (n = 413) had ongoing exposure beyond the first trimester. Cannabis exposure was associated with the primary composite outcome (25.9% in the cannabis exposure group vs 17.4% in the no exposure group; adjusted relative risk, 1.27 [95% CI, 1.07-1.49]) in the propensity score-weighted analyses after adjustment for sociodemographic characteristics, body mass index, medical comorbidities, and active nicotine use ascertained via urine cotinine assays. In a 3-category cannabis exposure model (no exposure, exposure only during the first trimester, or ongoing exposure), cannabis use during the first trimester only was not associated with the primary composite outcome; however, ongoing cannabis use was associated with the primary composite outcome (adjusted relative risk, 1.32 [95% CI, 1.09-1.60]). Conclusions and Relevance: In this multicenter cohort, maternal cannabis use ascertained by biological sampling was associated with adverse pregnancy outcomes related to placental dysfunction.

Does Labetalol Trigger False Positive Drug Testing Results?

OBJECTIVES: Labetalol, an α- and ß-adrenergic antagonist used to treat hypertension in pregnancy has been blamed for causing false-positive amphetamine and methamphetamine results. In this study, we tested 3 concentrations of labetalol prepared with 4 specimen types (urine, plasma, meconium, and umbilical cord tissue), for amphetamine, methamphetamine, and several other drugs with screen and confirmation tests. METHODS: Residual drug-free specimens were pooled. Labetalol hydrochloride dissolved in methanol was used to prepare spikes in triplicate per specimen type (2.7, 50, and 100 µM), which were tested with 41 previously validated drug tests performed by immunoassay or liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: Labetalol triggered false-positive amphetamine and methamphetamine results by immunoassay in meconium but did not trigger positive results for any of the targeted drugs or drug metabolites tested by LC-MS/MS. No positive results were generated by any immunoassay or LC-MS/MS test included in the study, when challenged with high concentrations of labetalol in urine, plasma, or umbilical cord tissue. CONCLUSIONS: In summary, false-positive results can be generated by labetalol when tested by immunoassay, but false-positive results are not expected when testing is performed by highly specific analytical approaches such as LC-MS/MS.

Can Umbilical Cord and Meconium Results Be Directly Compared? Analytical Approach Matters.

Maternal drug use during pregnancy is a significant concern. Drug-exposed newborns are often born premature and may suffer from birth defects, neonatal abstinence syndrome and cognitive and developmental delays. Because of this, testing of neonatal specimens is carried out to assess fetal drug exposure during pregnancy. Umbilical cord tissue (UC) and meconium are commonly used specimens for this purpose. However, comprehensive studies comparing drug positivity rates and concentration in the two specimen types are lacking. To this end, 4,036 paired UC and meconium specimens originating from 13 states within the USA were identified, and retrospective analysis of drug positivity rates and drug concentration was performed for 31 analytes in 5 drug classes. Testing for 11-Nor-9-carboxy-tetrahydrocannabinol (THC-COOH) is a separate orderable for UC specimen at our laboratory, so a second data set was created for evaluation of this drug analyte with 2,112 paired UC and meconium specimens originating from 11 states. Testing of UC was performed by semi-quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) assays, whereas, for meconium, an immunoassay-based screening preceded LC-MS-MS confirmation tests. Results generated for UC and meconium specimens were therefore compared for a total of 32 drug analytes from 6 drug classes. Drug concentrations for analytes were higher in meconium compared to UC, with the exception of phencyclidine. Despite this, the positivity rates for individual analytes were higher in UC, with the exception of THC-COOH and cocaine. Furthermore, analysis for multidrug positivity revealed that THC-COOH and opioids were the most common multidrug combination detected in both matrices. In conclusion, this study suggests that for most drug compounds, UC was more analytically sensitive to assess neonatal drug exposure by current methodologies. Additionally, by demonstrating that meconium has higher drug concentrations for most compounds, this study sets the stage for developing more sensitive assays in meconium.

Deceptively Simple: Can Urine Samples from CLIA-Waived Urine Drug Screen Devices Be Reused for Confirmatory Testing?

BACKGROUND: Many low-complexity urine drug screen (UDS) devices are approved by the Food and Drug Administration as waived under Clinical Laboratory Improvement Amendments (CLIA) criteria. Labeling instructs patients to urinate directly into the device and also states that positive results should be confirmed. However, the device itself may pose a risk of drug adsorption and/or specimen contamination that could affect results in confirmatory assays if specimens are reused. Collecting urine in a separate container before performing the UDS would reclassify the test as nonwaived, negating the conveniences of a CLIA-waived test. Also, patients may be unable or unwilling to urinate in an additional container for confirmatory testing. This study examined reusing urine from a UDS device (NexScreen) for confirmatory testing. METHODS: 25 patient specimens were pooled and verified to be drug-free. To evaluate drug leaching from the UDS device, 30 mL of this pool was incubated in NexScreen cups, followed by confirmatory testing. To evaluate drug adsorption, 14 representative analytes were spiked slightly over the NexScreen positivity cutoffs, followed by incubation in NexScreen cups and confirmation testing. RESULTS: All negative samples incubated in NexScreen cups remained negative upon confirmation testing, indicating that NexScreen test strips do not contaminate the specimen. For the drug adsorption experiment, 11 of 14 analytes had recoveries of at least 95%, whereas buprenorphine and 11-nor-9-carboxy-tetrahydrocannabinol recovered at 94% and 87%, respectively, suggesting minor adsorption. All analytes recovered above their respective confirmation cutoffs. CONCLUSIONS: Urine aliquots from NexScreen cups may be used for confirmatory testing.

Nicotine and Tobacco Alkaloid Testing and Challenges: Lessons Learned From a College of American Pathologists Proficiency Testing Survey.

CONTEXT.­: Consequences related to nicotine (NIC) use remain a major health concern, leading to demand for testing to detect NIC, metabolites such as cotinine (COT), and related tobacco alkaloids, including anabasine (ANAB). NIC-related testing is not standardized among laboratories, nor are there clinical or regulatory guidelines to inform decisions such as appropriate screening cutoffs or limits of quantitation. OBJECTIVE.­: To evaluate analytical performance and reporting practices of laboratories that perform NIC-related testing by reviewing participant responses to the Nicotine and Tobacco Alkaloid (NTA) Proficiency Testing Survey. DESIGN.­: NTA results were retrieved from 2017 (the first year of the survey) through 2020. Survey participants, methodologies, and results were evaluated for all analytes, and simulated grading was performed for COT. Additional data, including limits of quantitation, qualitative cutoffs, and reasons for testing, were reviewed. RESULTS.­: Participant growth was steady for qualitative COT testing. Participation was stable for NIC, ANAB, and quantitative COT testing. Overall, participants performed well on survey challenges. However, reporting thresholds were widely divergent, ranging from 10 to 3000 ng/mL and 0.5 to 300 ng/mL, respectively, for qualitative and quantitative COT testing. Screening cutoffs were as high as 100 ng/mL for ANAB and 1000 ng/mL for NIC. CONCLUSIONS.­: Although participating laboratories performed well on the NTA Survey, the wide diversity of qualitative and quantitative reporting thresholds creates substantial risk for misinterpretation of results, and could lead to analytical concerns such as excessively high false-negative or false-positive rates. NIC-related testing would benefit from evidence-based guidelines to drive standardization of reporting.

Analysis of Mitragynine and Speciociliatine in Umbilical Cord by LC-MS-MS for Detecting Prenatal Exposure to Kratom.

Kratom is an herbal drug that is legal in the USA. While it is marketed as a safer alternative to opioids, it can cause opioid-like withdrawal symptoms when discontinued after regular use. Several case studies have shown that kratom exposure in utero can lead to symptoms in newborns consistent with neonatal abstinence syndrome. Here, we present a validated method for the detection of kratom in umbilical cord by liquid chromatography--tandem mass spectrometry. The umbilical cord is homogenized in solvent and kratom analytes are purified by solid phase extraction (strong cation exchange). Diastereomeric kratom alkaloids mitragynine (MG), speciociliatine (SC), speciogynine and mitraciliatine are separated by reverse phase chromatography on a phenyl-hexyl column. Applying this method to residual umbilical cords submitted to our laboratory for drug testing, 29 positive specimens exhibiting varied kratom analyte distributions were observed. MG and SC were the most abundant kratom analytes and were selected as biomarkers of kratom exposure. A cutoff concentration of 0.08 ng/g was established for both MG and SC.

Umbilical Cord Collection and Drug Testing to Estimate Prenatal Substance Exposure in Utah.

OBJECTIVE: Our primary objective was to estimate statewide prenatal substance exposure based on umbilical cord sampling. Our secondary objectives were to compare prevalence of prenatal substance exposure across urban, rural, and frontier regions, and to compare contemporary findings to those previously reported. METHODS: We performed a cross-sectional prevalence study of prenatal substance exposure, as determined by umbilical cord positivity for 49 drugs and drug metabolites, through the use of qualitative liquid chromatography-tandem mass spectrometry. All labor and delivery units in Utah (N=45) were invited to participate. Based on a 2010 study using similar methodology, we calculated that a sample size of at least 1,600 cords would have 90% power to detect 33% higher rate of umbilical cords testing positive for any substance. Deidentified umbilical cords were collected from consecutive deliveries at participating hospitals. Prevalence of prenatal substance exposure was estimated statewide and by rurality using weighted analysis. RESULTS: From November 2020 to November 2021, 1,748 cords (urban n=988, rural n=384, frontier n=376) were collected from 37 hospitals, representing 92% of hospitals that conduct 91% of births in the state. More than 99% of cords (n=1,739) yielded results. Statewide, 9.9% (95% CI 8.1-11.7%) were positive for at least one substance, most commonly opioids (7.0%, 95% CI 5.5-8.5%), followed by cannabinoid (11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) (2.5%, 95% CI 1.6-3.4%), amphetamines (0.9%, 95% CI 0.4-1.5), benzodiazepines (0.5%, 95% CI 0.1-0.9%), alcohol (0.4%, 95% CI 0.1-0.7%), and cocaine (0.1%, 95% CI 0-0.3%). Cord positivity was similar by rurality (urban=10.3%, 95% CI 8.3-12.3%, rural=7.1%, 95% CI 3.5-10.7%, frontier=9.2%, 95% CI 6.2-12.2%, P=.31) and did not differ by substance type. Compared with a previous study, prenatal exposure to any substance (6.8 vs 9.9%, P=.01), opioids (4.7 vs 7.0% vs 4.7%, P=.03), amphetamines (0.1 vs 0.9%, P=.01) and THC-COOH (0.5 vs 2.5%, P<.001) increased. CONCLUSION: Prenatal substance exposure was detected in nearly 1 in 10 births statewide.

Association of Cannabis Use With Nausea and Vomiting of Pregnancy.

Our objective was to evaluate whether cannabis use was associated with nausea and vomiting in early pregnancy. Participants from nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be) enrolled from October 2010 through September 2013 with a PUQE (Pregnancy-Unique Quantification of Emesis) questionnaire and an available stored urine sample from the first study visit (median gestational age 12 weeks) were included. Cannabis exposure was ascertained by urine immunoassay for 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH); positive results were confirmed with liquid chromatography tandem mass spectrometry. The primary outcome was moderate-to-severe nausea by the PUQE score. Overall, 9,250 participants were included, and 5.8% (95% CI 5.4-6.3%) had detectable urine THC-COOH. In adjusted analyses, higher THC-COOH levels were associated with greater odds of moderate-to-severe nausea (20.7% in the group with THC-COOH detected vs 15.5% in the group with THC-COOH not detected, adjusted odds ratio 1.6, 95% CI 1.1-2.2 for a 500 ng/mg Cr THC-COOH increment).

LC-MS/MS Method for Measurement of Thiopurine Nucleotides (TN) in Erythrocytes and Association of TN Concentrations With TPMT Enzyme Activity.

Monitoring concentrations of thiopurine metabolites is used clinically to prevent adverse effects in patients on thiopurine drug therapy. We developed a LC-MS/MS method for the quantification of 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in red blood cells (RBCs). This method utilizes an automated cell washer for RBC separation from whole blood samples and washing of the separated RBCs. The lower limit of quantification of the method was 0.2 µmol/L for 6-TG (∼50 pmol/8 × 108 RBC) and 4 µmol/L for 6-MMP (∼1,000 pmol/8 × 108 RBC). The total imprecision of the assay was <3.0%. The upper limit of linearity for 6-TG and 6-MMP was 7.5 µmol/L and 150 µmol/L, respectively. The stability of the thiopurine metabolites under pre- and post-analytically relevant conditions was also evaluated. A good agreement was observed between this method and validated LC-MS/MS methods from three laboratories, except for ∼40% low bias for 6-MMP observed in one of the methods. The assessment of the association between 6-TG and 6-MMP concentrations with thiopurine S-methyltransferase (TPMT) phenotype and genotype demonstrated a statistically significant difference in the thiopurine metabolite concentrations between the TPMT groups with normal and intermediate activity of 6-MMP (p < 0.0001), while the difference in 6-TG concentrations was statistically not significant (p = 0.096). Among the samples with normal TPMT activity, higher concentrations of 6-MMP (p = 0.015) were observed in pediatric samples than in the samples of adults. No statistically significant differences were observed in the distributions of 6-TG and 6-MMP concentrations among the evaluated genotypes.

Clinical pharmacogenomic testing and reporting: A technical standard of the American College of Medical Genetics and Genomics (ACMG).

Pharmacogenomic testing interrogates germline sequence variants implicated in interindividual drug response variability to infer a drug response phenotype and to guide medication management for certain drugs. Specifically, discrete aspects of pharmacokinetics, such as drug metabolism, and pharmacodynamics, as well as drug sensitivity, can be predicted by genes that code for proteins involved in these pathways. Pharmacogenomics is unique and differs from inherited disease genetics because the drug response phenotype can be drug-dependent and is often unrecognized until an unexpected drug reaction occurs or a patient fails to respond to a medication. Genes and variants with sufficiently high levels of evidence and consensus may be included in a clinical pharmacogenomic test; however, result interpretation and phenotype prediction can be challenging for some genes and medications. This document provides a resource for laboratories to develop and implement clinical pharmacogenomic testing by summarizing publicly available resources and detailing best practices for pharmacogenomic nomenclature, testing, result interpretation, and reporting.

Concordance of Umbilical Cord Drug Screening in Multiple Births: Experience from a Reference Laboratory and Academic Medical Center.

The objective of this study was to review the results of umbilical cord drug screening in twins and triplets (multiples) to compare the detected drug(s) and/or drug metabolite(s). Results that did not agree between multiples were considered mismatched and investigated. A retrospective analysis was conducted using de-identified data from a national reference laboratory, and results were compared with data from an academic medical center, where detailed medical chart review was performed. Umbilical cord was analyzed for stimulants, sedatives, opioids and other drugs and metabolites. For the reference laboratory dataset, 23.3% (n = 844) of 3,616 umbilical cords from twins (n = 3,550) or triplets (n = 66) were positive for one or more drugs and/or metabolites. Of these, mismatched results were identified for 37 sets of twins (2.1%) and no sets of triplets. The most frequent mismatches were found in opioids (n = 24), with morphine (n = 5) being the most mismatched of any single analyte in the panel. Mismatches for the marijuana metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (9-COOH-THC) in the reference laboratory dataset occurred in 6 of 737 sets of twins (0.8%) and no triplets. For the academic medical center dataset, 21.9% (n = 57) of 260 umbilical cords tested positive for one or more drugs and/or metabolite(s). Of these, four mismatches (3.2%) were identified, including 9-COOH-THC (n = 2), phentermine (n = 1) and oxycodone (n = 1), all involving twins. All involved cases where the discrepant analyte was likely present in the negative twin but either slightly below the reporting cutoff threshold or failed analytical quality criteria. Mismatched results of umbilical cord drug screening occur in less than 4% of twins and most often occur when the analyte is slightly above the reporting cutoff in just one infant.

Tobacco and Cannabis Use During Pregnancy.

OBJECTIVES: Nicotine (NIC) use during pregnancy can influence markers used in biochemical maternal serum screening. This study was designed to determine prevalence of disclosed tobacco smokers in our patient population and to compare disclosed tobacco smoking status with the presence of serum nicotine and a common tetrahydrocannabinol (THC) metabolite. METHODS: A deidentified dataset of disclosed smoking status for quadruple (Quad) screens was obtained. Residual serum submitted for Quad screens was obtained from frozen storage and analyzed for NIC and THC metabolites. RESULTS: Of specimens that had corresponding responses to the smoking history question on the patient history form, 7.2% (n = 1,783 of 24,611) specified that the patient was a tobacco smoker. Of the 271 specimens biochemically analyzed for NIC and THC metabolites, disclosed tobacco smokers had the highest prevalence of detectable NIC and THC metabolites. THC product use was most prevalent in patients categorized as probable tobacco smokers based on cotinine concentrations, as well as in younger patients. CONCLUSIONS: Prevalence and concentration of NIC and THC metabolites vary based on disclosed tobacco smoker status. Biochemical testing may increase sensitivity for the identification of NIC and THC status over self-reporting.

Quantification of prenatal marijuana use: evaluation of the correlation between self-report, serum, urine and umbilical cord assays among women delivering at two urban Colorado hospitals.

BACKGROUND AND AIMS: To estimate during pregnancy correlations between frequency of self-reported use of marijuana and quantified marijuana metabolite in biospecimens including urine, sera and umbilical cord homogenate. DESIGN: Prospective cohort. SETTING: Two urban hospitals in Colorado with legal recreational and medicinal marijuana. PARTICIPANTS: Pregnant women (<16 weeks gestation) self-reporting marijuana use. MEASUREMENTS: Participants completed a written self-report survey and provided biospecimens at <16 weeks gestation (n = 46), 18 to 22 weeks gestation (n = 43), 32 to 36 weeks gestation (n = 39), and delivery (n = 37). Self-reported marijuana use frequency was calculated based on past-month days of use multiplied by number of daily uses. Maternal urine and sera were tested for presence (>5 ng/mL) of 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH). Liquid chromatography tandem mass spectrometry quantified THC-COOH in umbilical cord homogenate (ng/g). Last marijuana use by any measure was recorded to evaluate the time frame over which THC-COOH remains detectable (>0.10 ng/g) in cord. FINDINGS: From December 2017 through May 2019, 51 pregnant women enrolled, and 46 were included in analyses (2 withdrew and 3 had a spontaneous abortion). The majority were normal weight, White or Black race, and insured by Medicaid. At the time of enrollment between 7 to 15 weeks' gestation, 87% had ongoing use by self-report, or positive urine or serum. The majority (33 [66%]) stopped using before delivery. Sera and urine results were strongly correlated with self-reported use frequency (Spearman correlation coefficient [r] range 0.70-0.87 across visits, P < 0.001), and with each other. There was only one positive cord result when use stopped before 22 weeks. Frequency of self-reported marijuana use at delivery had strong correlation with quantified cord THC-COOH (r = 0.80, 95% CI = 0.62-0.89). CONCLUSIONS: Quantified umbilical cord THC-COOH appears to strongly correlate with frequency of maternal marijuana use in the last month of pregnancy. Earlier use can be measured by either quantitative urine or serum assay.

Endogenous and iatrogenic sources of variability in response to opioid therapy in Post-Surgical and injured orthopedic patients.

BACKGROUND: Hydrocodone is the most prescribed opioid in the US. The objective was to evaluate associations between genetic, intrinsic, and extrinsic patient factors, plasma hydrocodone and metabolites, common side effects, and pain scores in a cohort of orthopedic surgery patients. METHODS: Data for each patient was collected by review of the electronic hospital record (EHR), and patient interview. Patients were recruited from those with trauma or undergoing scheduled elective surgery for total knee replacement or total hip at the University of Louisville Hospital, Baptist East Hospital, and Jewish Hospital, Louisville, KY. Plasma opiate concentrations and a targeted genotyping panel was performed. RESULTS: There were statistically significant correlations with daily (p < 0.001) and total dose (p = 0.002) of hydrocodone in hospital and duration of opioid therapy. The length of opioid administration was significantly shorter in CYP2D6 EM/UM versus CYP2D6 PM/IM patients (p = 0.018). Subjects with the OPRM1 c.118G variant were also on opioids longer (p = 0.022). The effect of co-administration of a CYP2D6 inhibitor had a significant effect on the length of opioid therapy (P < 0.001). And not surprisingly the effect of the inhibitor adjusted CYP2D6 phenotype was greater in both the hospital stay period and days of opioid use post hospital discharge (p < 0.001). CONCLUSIONS: Based on this study, patients should be evaluated for the use of inhibitors of CYP2D6, during hydrocodone therapy can alter the phenotype of the patient (phenocopy) and increase the probability that the patient will be on opioids for longer periods of time.

Potential Utility of Pre-Emptive Germline Pharmacogenetics in Breast Cancer.

Patients with breast cancer often receive many drugs to manage the cancer, side effects associated with cancer treatment, and co-morbidities (i.e., polypharmacy). Drug-drug and drug-gene interactions contribute to the risk of adverse events (AEs), which could lead to non-adherence and reduced efficacy. Here we investigated several well-characterized inherited (germline) pharmacogenetic (PGx) targets in 225 patients with breast cancer. All relevant clinical, pharmaceutical, and PGx diplotype data were aggregated into a single unifying informatics platform to enable an exploratory analysis of the cohort and to evaluate pharmacy ordering patterns. Of the drugs recorded, there were 38 for which high levels of evidence for clinical actionability with PGx was available from the US FDA and/or the Clinical Pharmacogenetics Implementation Consortium (CPIC). These data were associated with 10 pharmacogenes: DPYD, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, G6PD, MT-RNR1, SLCO1B1, and VKORC1. All patients were taking at least one of the 38 drugs and had inherited at least one actionable PGx variant that would have informed prescribing decisions if this information had been available pre-emptively. The non-cancer drugs with PGx implications that were common (prescribed to at least one-third of patients) included anti-depressants, anti-infectives, non-steroidal anti-inflammatory drugs, opioids, and proton pump inhibitors. Based on these results, we conclude that pre-emptive PGx testing may benefit patients with breast cancer by informing drug and dose selection to maximize efficacy and minimize AEs.