Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedure for screening of urine specimens for 100 analytes relevant in drug-facilitated crime (DFC).

In recent years, drug-facilitated crime (DFC) has become an increasing problem. A minimum list of 80 analytes to be monitored in such cases has been proposed by the Society of Forensic Toxicologists (SOFT) including the recommended minimum performance limits (RMPL). In the present study, two liquid chromatography-tandem mass spectrometry-based screening procedures, one in positive (method I) and one in negative (method II) electrospray ionization mode were developed and validated. Gradient elution was performed on a ZORBAX Eclipse XDB-C18 column after protein precipitation of the urine samples. Detection was carried out in the scheduled multiple reaction monitoring (MRM) mode monitoring two transitions per compound. A total of 100 analytes (91 basic in method I and nine acidic in method II) could be identified using the described procedure. No interferences were observed in 30 tested blank urine samples. The RMPLs were achieved for all analytes and ranged from 1 ng/mL for fentanyl to 10 µg/mL for γ-hydroxybutyrate (GHB). Matrix effects (ME) were evaluated using the same 30 urine samples and ranged from -90 % for tetrazepam to >6,000 % for the 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH). The relative standard deviations of ME were below 25 % for the vast majority of analytes. Results for urine specimens from nine authentic DFC cases were always negative with exception of drugs prescribed to the victims. Reanalysis with the developed procedure of 24 urine samples, with a positive screening result during routine clinical toxicology analysis, confirmed the routine findings. In an excretion study after a single oral doxylamine dose (30 mg), the parent drug and its nor metabolite could be detected in urine specimens from a young female volunteer for 10 days. The developed procedure allows a selective and sensitive screening of urine samples for almost all recommended analytes relevant in DFC cases.

Bioavailability of Cariban® Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.

BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.

A simple and sensitive LC-MS/MS method for determination of doxylamine in human plasma and its application in a bioequivalence study in healthy Chinese volunteers.

A simple, rapid, sensitive and specific LC-MS/MS method was developed and validated for the quantitative determination of doxylamine in human plasma, using isotope doxylamine-d5 as internal standard (IS). The detection was conducted on a QTRAP 5500 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. Quantification was achieved by positive electrospray ionization containing multiple reaction monitoring (MRM) transitions of m/z 271.0→182.0 for doxylamine and m/z 276.2→187.3 for IS. The mobile phase A was methanol, and mobile phase B was 20 mM ammonium acetate (0.2 % formic acid) in water, using a gradient elution procedure at a flow rate of 0.6 mL/min. The method was validated with a sensitivity of 0.500 ng/mL and a linear concentration range of 0.500-200 ng/mL. The inter-batch precision (%CV) was less than 5.4 %, and the accuracy deviation (%RE) ranged from - 10.6 % to 3.7 %; the inter-batch precision (%CV) was less than 6.6 %, and the accuracy deviation (%RE) was ranged from - 2.7 % to 0.1 %. The selectivity, sensitivity, extraction recovery, matrix effect, carryover, dilution reliability, stability and other characteristics were within the acceptable range. This validated method was successfully applied to a bioequivalence study that orally administered 25 mg of doxylamine succinate tablets in 60 healthy Chinese volunteers.

Systemic bioavailability and pharmacokinetics of the doxylamine-pyridoxine delayed-release combination (Diclectin).

BACKGROUND: Diclectin, composed of 10 mg doxylamine succinate (DOX) and 10 mg pyridoxine hydrochloride, is the drug combination of choice for the management of nausea and vomiting during pregnancy in Canada. However, there is large variability in its onset and duration of action among women. To understand and improve its effectiveness, the variability in the pharmacokinetics of the ingredients in this doxylamine succinate/pyridoxine hydrochloride combination must be studied. OBJECTIVES: To determine the pharmacokinetics of DOX and pyridoxine after oral administration of two tablets of this drug combination in the form of Diclectin and to calculate their respective relative bioavailability by comparison with intravenous administration in another population. METHODS: Eighteen nonpregnant, nonlactating, healthy females between 18 and 45 years of age were administered two tablets of Diclectin with 240 mL of water under empty stomach conditions. Blood samples were analyzed for DOX and pyridoxine along with its four active metabolites: pyridoxal, pyridoxal-5'-phosphate (PLP), pyridoxamine, and pyridoxamine-5'-phosphate using tandem mass spectrometry. For the purpose of this study, pharmacokinetic values for DOX and PLP were adjusted for body weight. RESULTS: The mean DOX-AUC0→∞ was calculated to be 3137.22 ± 633.57 ng·hr/mL (range, 2056.59-4376.06 ng·hr/mL). The mean PLP-AUC0→∞ was calculated to be 5513.10 ± 2362.35 ng·hr/mL (range, 1572.56-10,153.77 ng·hr/mL). Based on literature values of the PLP-AUC0→∞ after intravenous administration and data from the current study, the relative bioavailability of pyridoxine in Diclectin was calculated at 100%. CONCLUSION: There was a 2.1-fold variability in the DOX-AUC0→∞ and 6.5-fold variability in the PLP-AUC0→∞ after oral administration of 20 mg Diclectin. Using literature values and data from the current study, we estimated the oral bioavailability of pyridoxine to be 100%. Therefore, interindividual differences in metabolism, and not in bioavailability, may be important sources of variability that need to be addressed in dosing guidelines.

A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment.

INTRODUCTION: Doxylamine tablets are approved as an over-the-counter sleep aid. We developed a doxylamine succinate intranasal metered-dose delivery system with the expectation of a more rapid onset of action with reduced side-effect potential compared with the oral tablet. METHODS: This phase I study randomized 24 adults with chronic intermittent sleep impairment to receive either single doses of intranasal doxylamine succinate 3.2, 6.3, or 12.7 mg or doxylamine succinate 25-mg oral tablet. Doxylamine pharmacokinetics were assessed using noncompartmental methods; pharmacodynamics were evaluated using the Karolinska Sleepiness Scale (KSS) and numerous psychomotor tests. Adverse events (AEs) were monitored. RESULTS: None of the intranasal dose levels produced a mean maximum plasma concentration (Cmax) above the 50 ng/mL target level or a time to maximum concentration shorter than that of the oral tablet. At the highest intranasal dose, Cmax and area under the doxylamine concentration-time curve were approximately 25% of the values achieved with the oral dose. Variation in most pharmacokinetic parameters was higher with intranasal compared with oral dosing. A relationship between plasma doxylamine concentration and KSS change from baseline was evident for the 25-mg tablet and, to a lesser extent, for the 12.7-mg intranasal dose. Changes from baseline in psychomotor parameters did not show a relationship to intranasal dose, and did not distinguish between intranasal versus oral dosing. The most common AEs with intranasal dosing were nasal congestion, nasal dryness, and frontal headache. CONCLUSION: The nasal spray did not increase doxylamine absorption or systemic bioavailability compared with the oral tablet.

Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Doxylamine and diphenhydramine pharmacokinetics in women on low-dose estrogen oral contraceptives.

Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers.

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.

Pharmacokinetics of doxylamine, a component of Bendectin, in the rhesus monkey.

The elimination of doxylamine and metabolites was determined after iv administration of [14C]doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly increased and the polar doxylamine metabolites were significantly decreased as the iv doxylamine succinate dose was increased. The plasma elimination of gas chromatograph (GC)-detected doxylamine was determined after oral administration of Bendectin (doxylamine succinate and pyridoxine hydrochloride) at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose increased, the clearance of doxylamine decreased. A statistically evaluated fit of the oral data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data.

Pharmacokinetics of doxylamine given as Bendectin in the pregnant monkey and baboon.

The object of the present study was to determine the maternal plasma pharmacokinetics of doxylamine (the antihistamine component of Bendectin) following Bendectin administration. Bendectin was administered daily, po, at a dosage approximately 10 times the maximum human therapeutic dosage (7 mg/kg/day) throughout organogenesis (approximately days 22 through 50 of gestation) to three cynomolgus monkeys, four rhesus monkeys, and five baboons. Two pharmacokinetic experiments were performed in each animal, one on the first day of treatment and one on the last day of treatment. Although this study was not designed specifically as a teratologic examination, no morphologic abnormalities were observed when the fetuses were examined on approximately day 100 of gestation. A single-compartment, parallel first- and second-order elimination model was used to analyze the data. Although considerable interindividual variation was evident, no significant differences between species were observed when the half-life for the absorption of doxylamine from the gut or the elimination of doxylamine and metabolites from the plasma were compared. The plasma elimination half-lives and the clearance values were not altered by the 29 days of Bendectin treatment for any of the species. Only the half-life for the absorption of doxylamine in the baboon was reduced by daily dosing with Bendectin, but this did not alter doxylamine elimination. Thus, the pharmacokinetics of doxylamine administered as Bendectin were similar in the three nonhuman primate species examined and were not altered by repeated daily administration.

Critical appraisal of drug therapy for nausea and vomiting of pregnancy: II. Efficacy and safety of diclectin (doxylamine-B6).

Nausea and vomiting of pregnancy is the most common condition in pregnancy and affects up to 80% of all pregnant women. There are a large number of pharmacological agents that are effective for the treatment of nausea and vomiting associated with conditions such as motion sickness and gastrointestinal conditions; however, their use in pregnancy is limited by the lack of sufficient data on their potential teratogenic effects. The efficacy of the delayed-release combination of doxylamine and pyridoxine (Bendectin, Diclectin) has been shown in several randomized, controlled trials. The present review aims to refute the unsubstantiated beliefs that Diclectin is unsafe when used in the treatment of nausea and vomiting of pregnancy.

A comparative study of an in situ adapted diffusion cell and an in vitro Franz diffusion cell method for transdermal absorption of doxylamine.

In order to determine whether a drug shows the potential for percutaneous absorption, both in situ and in vitro studies are used. In vitro studies are good indicators of transdermal drug delivery, but the possibility exists that anatomical changes in excised skin can influence drug delivery. The aim of this study was to compare the in vitro Franz diffusion cell method with an in situ adapted diffusion cell method. A saturated aqueous solution of doxylamine succinate was used as model drug and the receptor phase was an isotonic Sörensen buffered solution. The in vitro permeation studies were conducted using vertical Franz diffusion cells with nude mice skin. For in situ studies, a diffusion cell was implanted under the dorsal skin of a nude mouse, simulating the in vitro method. Both in situ and in vitro experiments were conducted over a period of 12 h during which samples were collected every 90 min. The mean steady-state flux from Franz diffusion cells was 0.164+/-0.045 microg/cm2/h and flux determined by the in situ method was 0.113+/-0.034 microg/cm2/h. A statistical significant difference existed between the permeation results of the in vitro and in situ experimental methods. A subjective, semi-quantitative assessment of histological changes to excised nude mouse skin was done using light microscopy. This showed that excised skin undergoes sub-lethal injury (necrosis) during in vitro experiments, which may lead to increased permeability of the drug. It was noticed that in vitro and in situ permeation results showed very close correlation until approximately 4.5 h after commencement of experiments, after which, the permeation through excised skin increased. It was assumed that cell necrosis occurred to such an extent after approximately 4.5 h, that the barrier function of the stratum corneum decreased and permeation of the drug increased.

Studying the antiemetic effect of vitamin B6 for morning sickness: pyridoxine and pyridoxal are prodrugs.

Vitamin B6 has been known to possess antiemetic effects since 1942. This water soluble compound has several forms in the circulation including pyridoxine, pyridoxal, and pyridoxal phosphate. The active antiemetic form of vitamin B6 is unknown. This was a pre-specified substudy of a randomized, placebo-controlled trial comparing the antiemetic effect of the doxylamine-vitamin B6 combination (Diclectin®) (n = 131) to placebo (n = 126) in women with nausea and vomiting of pregnancy. Serum concentrations of pyridoxine, pyridoxal, and pyridoxal 5' phosphate (PLP) and doxylamine were measured on Days 4, 8, and 15. With Diclectin® exhibiting a significant antiemetic effect in pregnancy, serum concentrations of pyridoxine were unmeasurable in almost all patients and those of pyridoxal were undetectable in half of patients. In contrast, PLP was measurable at sustained, stable steady-state levels in all patients. Our data suggest that there is a correlation between PLP levels and PUQE score of morning sickness symptoms when pyridoxine and pyridoxal levels are undetectable, and hence they might be prodrugs of PLP, which may be the active antiemetic form of vitamin B6.

Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years.

To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride; implications for pharmacotherapy in pregnancy.

Most bioequivalence (BE) studies are conducted in males with the assumption that variability in pharmacokinetics is similar between the sexes. The purpose of this single-center, reference replicate study was to determine the effect of sex on the pharmacokinetics and BE of doxylamine-pyridoxine 10 mg-10 mg delayed-release tablets. Healthy males (n = 12) and non-pregnant females (n = 12) were administered two tablets, and blood sampling was conducted from 1 hour pre-dose until 72 hours post-dose. After 21 days, dose administration and blood sampling were re-conducted. All analytes were measured using liquid chromatography-tandem mass-spectrometry. Pharmacokinetic parameters were calculated for each study period using standard, non-compartmental methods, and differences were assessed using ANOVA. BE testing was conducted using the relative 90% confidence interval for the AUC0-t for each analyte. Females had significantly larger AUC0-t for doxylamine, 1,550 ng h/mL (coefficient of variance [CV = 19%]) versus 1,272 ng h/mL (CV = 21%; P ≤ .05), and pyridoxine, 35 ng h/mL, (CV = 43%) versus 25 ng h/mL (CV = 31%; P ≤ .05) compared to males. A higher Cmax for doxylamine was observed in females, 107 ng/mL (CV = 16%), compared to males, 86 ng/mL (CV = 15%) (P ≤ .05). BE testing did not demonstrate bioequivalence between males and females. Pharmacokinetic differences observed between the sexes have implications for future BE studies using doxylamine-pyridoxine.

Pharmacokinetic dose proportionality between two strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate film-coated tablets in fasting state: a single-dose, randomized, two-period crossover study in healthy volunteers.

BACKGROUND: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years. OBJECTIVE: The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects. STUDY DESIGN: This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study. SETTING: The study was conducted in a phase I clinical unit. SUBJECTS AND METHODS: A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration-time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG). RESULTS: In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration-time curve from time zero to time t (AUCt ) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2%; mean AUCt 817.33 ng·h/mL, CV 27.4%; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7%; mean AUCt 1630.85 ng·h/mL, CV 22.8%]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8% for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90% CI: 92.46, 105.83). The most common adverse event was somnolence. CONCLUSIONS: Exposure to doxylamine was proportional over the therapeutic dose range of 12.5-25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated.

Study on the conditions of use for Caribán(R) and other antiemetics in the treatment of nausea and vomiting during pregnancy / Estudio sobre las condiciones de uso de Caribán(R) y de otros antieméticos en el tratamiento de las náuseas y vómitos en el embarazo: estudio prospectivo observacional longitudinal

Objective: We performed a prospective observational study on the conditions of use of a medication, Caribán(R), and of other antiemetics for the treatment of nausea and vomiting in pregnancy (NVP). The study was practical in design, and its main objective was to determine the frequency of use of Caribán(R) in the treatment of NVP by analyzing conditions of use in daily clinical practice. Material and methods: The study population comprised 184 pregnant women with nausea and/or vomiting during the days preceding the first study visit. The patients attended up to 4 visits, 3 of which were face-to-face, and provided clinical follow-up data and data on the treatment used by means of an app. Data on treatment and the evaluation of nausea and vomiting were obtained every 24 hours using the Pregnancy-Unique Quantification of Emesis and Nausea score (PUQE). Results: The most frequently used initial regimen was 1 capsule every 8 hours. Data were available from the baseline visit and from the daily follow-up of 158 women (ie, 4982 daily evaluations). The mean score for severity of NVP was 5.69 points (mild) (SD, 1.8; range, 3-13) and the mean cumulative dose per woman throughout the follow-up was 34.61 capsules (6-197). NVP was mild in 72.48% of evaluations, moderate in 26.57%, and severe in 0.94%. Patients did not take medication in 54% (n=1969) of the mild daily episodes and in 14% of the moderate episodes. Mean consumption per daily episode was 1.74 (0-10) capsules per episode of mild NVP and 2.14 (0-35) capsules per episode of moderate NVP. Women who had NVP took Caribán(R) according to the app on 66.7% of the days with symptoms. Conclusions: The most common initial regimen prescribed was 1 capsule every 8 hours. Most of the episodes of NVP were mild, and on 50.85% of days with mild NVP, the women did not take medication. The mean daily dose per mild episode was 1.74 capsules. The patients reported having taken medication for moderate NVP in 86% of cases. The mean dose per episode was 2.14 capsules. The patients took Caribán(R) on 66.7% of days with NVP

Objetivo: El estudio sobre las condiciones de uso de Caribán(R) y otros antieméticos en el tratamiento de las náuseas y vómitos del embarazo (NVE) es un estudio observacional prospectivo de utilización de medicamentos diseñado con criterios pragmáticos que se plantea con el objetivo principal de determinar la frecuencia de uso de Caribán(R) en el tratamiento de las náuseas y vómitos del embarazo (NVE) analizando sus condiciones de uso en la práctica clínica diaria. Material y Metodos: Han participado 184 embarazadas con náuseas y/o vómitos en los días previos a la primera visita del estudio que atendieron hasta 4 visitas, tres de ellas presenciales, y facilitaron información del seguimiento clínico y del tratamiento utilizado mediante una aplicación telefónica. Se han recogido variables de tratamiento y la valoración de náuseas y vómitos cada 24 horas mediante la escala PUQE (PregnancyUniqueQuantification of Emesis and nausea). Resultados: La pauta de inicio más frecuentemente utilizada fue una capsula cada 8 horas. Existen datos de visita basal y de seguimiento diario de 158 embarazadas que suponen 4982 valoraciones diarias. La valoración media de la gravedad de las NVE es 5,69 puntos (LEVE), (SD 1,8, rango 3-13) y la dosis acumulada media por mujer durante todo el seguimiento 34,61 cápsulas ( 6-197). En el 72,48% de todas las valoraciones las NVE fueron leves, el 26,57% moderadas y el 0,94% graves. En el 54% (n=1969) de los episodios diarios leves y en el 14% de los moderados las gestantes no tomaron medicación. El consumo medio por cada episodio diario de NVE leve fue de 1,74 (0-10) cápsulas, mientras que en cada episodio moderado se utilizaron 2,14 (0-35) cápsulas. Las mujeres que tenían NVE tomaban Caribán(R) según la aplicación en el 66,7% de los días que tenían clínica. Conclusiones: La pauta de inicio prescrita mas frecuentemente fue una capsula cada 8 horas. La mayor parte de los episodios de NVE son leves, y en el 50.85% de los días con náuseas o vómitos leves las embarazadas no tomaron medicación. La dosis media por episodio/día leve es de 1,74 cápsulas. En los episodios diarios de NVE moderados el 86% de las embarazadas señalaron tomar la medicación siendo la dosis media por episodio de 2,14. El 66,7% de los días en que las mujeres tenían NVE tomaban Caribán(R)

Comparing the pharmacokinetics of doxylamine/pyridoxine delayed-release combination in nonpregnant women of reproductive age and women in the first trimester of pregnancy.

Although Diclectin (doxylamine/pyridoxine delayed-released combination) is widely used in Canada, its pharmacokinetics (PK) during pregnancy has never been described. The objective of this study was to compare the PK of doxylamine/pyridoxine delayed-released combination in pregnant versus nonpregnant women. The apparent clearances (CL) of doxylamine and pyridoxal 5'-phosphate (PLP; the active metabolite of vitamin B(6) ) during the first-trimester pregnancy in women who participated in a Diclectin randomized trial were compared with those of healthy, adult, nonpregnant women who participated in a voluntary PK trial. Eighteen nonpregnant women were compared with 50 pregnant women who were treated with Diclectin. There was no difference in the apparent CL of doxylamine in women in their first trimester of pregnancy when compared with nonpregnant women on day 4 (median = 196.7 vs 249.5 mL/h/kg, respectively, P = .065), day 8 (median = 248.4 vs 249.5 mL/h/kg, respectively, P = .82), and day 15 (median = 200.9 vs 249.5 mL/h/kg, respectively, P = .55). No difference was found in the apparent CL of PLP on day 15 (median = 342.3 vs 314.7 mL/h/kg, respectively, P = .92). There was no pregnancy-induced effect in the apparent CL of either doxylamine or PLP in women during the first trimester of pregnancy despite the existence of morning sickness.

Food effects on the pharmacokinetics of doxylamine hydrogen succinate 25 mg film-coated tablets: a single-dose, randomized, two-period crossover study in healthy volunteers.

BACKGROUND: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions. STUDY DESIGN: This was a single-center, randomized, single-dose, laboratory-blinded, two-period, two-sequence, crossover study. SETTING: The study was conducted in a phase I clinical unit. SUBJECTS AND METHODS: A single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. RESULTS: In total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug concentration [C(max)] 118.21 ng/mL, coefficient of variation [CV] 19.2%; mean area under the plasma concentration time curve from time zero to time t [AUC(t)] 1746.97 ng · h/mL, CV 31.6%) and in the fed state (mean C(max) 120.99 ng/mL, CV 15.0%; mean AUC(t) 1712.20 ng · h/mL, CV 26.7%). No statistically significant between-treatment differences were observed for any of the pharmacokinetic parameters under study. The fed : fasting ratios of the geometric least squares means with corresponding 90% confidence intervals for C(max) and AUC(t) were within the range of 80-125%. CONCLUSION: High-fat, high-calorie food intake does not affect the kinetics of doxylamine in healthy subjects. The drug was safe and well tolerated by the subjects in this study.

Simultaneous determination of dextromethorphan, dextrorphan and doxylamine in human plasma by HPLC coupled to electrospray ionization tandem mass spectrometry: application to a pharmacokinetic study.

In the present study, a fast, sensitive and robust method to quantify dextromethorphan, dextrorphan and doxylamine in human plasma using deuterated internal standards (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction (LLE) using diethyl-ether/hexane (80/20, v/v). Extracted samples were analyzed by high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase (acetonitrile/water/formic acid (90/9/1, v/v/v) during 4.0min at a flow-rate of 1.5 mL min⁻¹ into a Phenomenex Gemini® C18, 5 µm analytical column (150 × 4.6 mm i.d.). The calibration curve was linear over the range from 0.2 to 200 ng mL⁻¹ for dextromethorphan and doxylamine and 0.05 to 10 ng mL⁻¹ for dextrorphan. The intra-batch precision and accuracy (%CV) of the method ranged from 2.5 to 9.5%, and 88.9 to 105.1%, respectively. Method inter-batch precision (%CV) and accuracy ranged from 6.7 to 10.3%, and 92.2 to 107.1%, respectively. The run-time was for 4 min. The analytical procedure herein described was used to assess the pharmacokinetics of dextromethorphan, dextrorphan and doxylamine in healthy volunteers after a single oral dose of a formulation containing 30 mg of dextromethorphan hydrobromide and 12.5mg of doxylamine succinate. The method has high sensitivity, specificity and allows high throughput analysis required for a pharmacokinetic study.