A Uhplc–Ms/Ms Method for the Quantification of Δ9-tetrahydrocannabinol and Cannabidiol in Decoctions and in Plasma Samples for Therapeutic Monitoring of Medical Cannabis

Fucile, Carmen; Manfredini, Luca; Grandis, Elisa De; Gherzi, Marcella; Martelli, Antonietta; Tripodi, Gino; Mattioli, Francesca; Cangemi, Giuliana

doi:10.4155/bio-2018-0184

Cited by 16 publications

(14 citation statements)

References 21 publications

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“…To measure plasma trough steady-state (C SS, Min ) cannabinoid levels, blood was collected on Visits 2–5 into lithium heparin Barricor vacutainers and centrifuged for 10 min in a clinical centrifuge (1,500 rpm) (12). These plasma samples (200 μL) were prepared and analyzed for CBD, CBC, and THC levels according to a validated liquid chromatography-mass spectrometry (LC-MS/MS) method that while developed independently in our lab is similar to a previously reported validated plasma cannabinoid assay (7, 13). All samples were stored at −70°C prior to analysis.…”

Section: Methodsmentioning

confidence: 99%

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

et al. 2019

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Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ 9 -tetrahydrocannabinol (THC): CBD up to 10–12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (C ss, Min ) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10–12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. C SS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. C SS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, C SS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5–6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

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Section: Methodsmentioning

confidence: 99%

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

et al. 2019

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“…Thus, plasma levels may be a strategy to guide CBD doses for adult patients with epilepsy. Assays have been developed and validated and may be of clinical utility in the future (32,45,46).…”

Section: Gaps In Knowledge: Cbd For Epilepsy In Adults Long-term Safmentioning

confidence: 99%

Cannabidiol in the Treatment of Epilepsy: A Focused Review of Evidence and Gaps

et al. 2020

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Approximately one third of epilepsy patients do not become seizure free with antiseizure medications. This treatment gap motivates research for new therapeutic options, such as cannabidiol (CBD). CBD differs from other cannabis derivatives because of its consistent efficacy and lack of a psychoactive effect. CBD can be recommended as adjunctive therapy in patients with Dravet and Lennox-Gastaut syndromes. The most common adverse effects (AEs) are drowsiness, reduced appetite, diarrhea, and vomiting. Transaminase elevation is the most common AE that leads to CBD discontinuation. Coadministration with valproate may increase the risk of hepatotoxicity. The combination of CBD and clobazam may increase both the effectiveness and the risk of AEs associated with these drugs. The most striking gaps in knowledge are the efficacy and optimal dose of CBD for adults with focal epilepsies, the long-term safety of CBD use, and strategies to improve access to CBD for people living with epilepsy.

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“…Few of them [28,29,[31][32][33] have been validated for their suitability for TDM of medical cannabis on plasma samples. The disadvantage of TDM based on plasma samples is represented by the discomfort caused to patients to obtain venous samples by using sampling procedures that cannot be applied at all to pediatrics patients and/or newborns, limiting the widespread of TDM in such population.…”

Section: Discussionmentioning

confidence: 99%

“…Mass spectrometric conditions were those previously described [ 31 ]. Briefly, ionization was achieved using atmospheric pressure chemical ionization (APCI) in the positive ion mode and analytes were detected using selective reaction monitoring (SRM) of the specific transitions, THC and CBD [M + H] + 315.2 → 193.1 m / z and their deuterated IS [M + H] + 318.2 → 196.1 m / z , respectively, with a dwell time of 249 ms.…”

Section: Methodsmentioning

confidence: 99%

“…Starting from a previously published method [31], we added an online sample purification step. On pump 1 a solid phase extraction (SPE) online purification was carried out on a TurboFlow HTLC C18-XL column (0,5 x 50 mm, Thermo Fisher Scientific, Milan, Italy) with mobile phase A consisting of 100% water, mobile phase B of acetonitrile: isopropanol: acetone 1:1:1 and mobile phase C of 0.2% formic acid in H 2 O:MeOH 20:80.…”

Section: Chromatographic Separationmentioning

confidence: 99%

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Cannabidiol Determination on Peripheral Capillary Blood Using a Microsampling Method and Ultra-High-Performance Liquid Chromatography Tandem Mass Spectrometry with On-Line Sample Preparation

et al. 2020

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The aim of this work is to evaluate volumetric absorptive microsampling (VAMS) from capillary blood as an alternative strategy for therapeutic drug monitoring (TDM) in patients treated with the newly available GW-purified form of cannabidiol (Epidiolex®). A fast ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) coupled to an online sample preparation system analysis was carried out on a Thermo Scientific Ultimate 3000 LC system coupled to a TSQ Quantiva triple quadrupole for the quantification of cannabidiol (CBD) and, in addition, delta-9-tetrahydrocannabinol (Δ9-THC). After validation using European Medicine Agency (EMA) guidelines the method was applied to samples obtained by finger prick of five pediatric patients treated with Epidiolex® and the results were compared to those obtained from venous blood and plasma. The method is linear in the range of 1–800 µg/L for both CBD and THC with intra- and inter-day precisions ranging from 5% to 14% and accuracies from −13% to +14% starting from 30 µL of sample. Stability in VAMS is ensured for up to 4 weeks at 25 °C thus allowing simple delivery. There was no difference (p = 0.69) between concentrations of CBD measured from VAMS sampled from capillary or venous blood (range: 52.19–330.14 or 72.15–383.45 µg/L) and those obtained from plasma (range: 64.3–374.09 µg/L) The VAMS-LC-MS/MS method represents a valid alternative strategy for therapeutic drug monitoring of patients treated with Epidiolex®.

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A Uhplc–Ms/Ms Method for the Quantification of Δ9-tetrahydrocannabinol and Cannabidiol in Decoctions and in Plasma Samples for Therapeutic Monitoring of Medical Cannabis

Cited by 16 publications

References 21 publications

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study

Cannabidiol in the Treatment of Epilepsy: A Focused Review of Evidence and Gaps

Cannabidiol Determination on Peripheral Capillary Blood Using a Microsampling Method and Ultra-High-Performance Liquid Chromatography Tandem Mass Spectrometry with On-Line Sample Preparation

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