Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide.

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, ß = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, ß = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

Off-label pharmacological treatment for neuropathic pain: A Delphi study by the Spanish Pain Society Neuropathic Pain Task Force.

OBJECTIVES: The use of off-label pharmacotherapies for neuropathic pain (NP) is growing relating to the many unmet needs of patients. However, clinical guidelines fail to address it, and the available evidence is sparse and fragmented. We arranged a formal expert consensus to address this controversial issue and provide some guidance on judicious use. METHODS: A two-round standard Delphi survey that involved pain clinic specialists with experience in the research and management of NP was done over an ad hoc 40-item questionnaire prepared by the authors. Consensus on each statement was defined as at least either 80% endorsement or rejection after the second round. RESULTS: Forty-three and thirty-seven panelists participated in the first and second round, respectively. Consensus was reached in 34 out of 40 statements. Endorsed alternatives for unresponsive patients include non-gabapentinoid antiepileptics (oxcarbazepine and eslicarbazepine), venlafaxine, intravenous lidocaine (when doses can be optimized), and some vaporized cannabinoids (under appropriate surveillance). In addition, lacosamide, low-dose naltrexone, propofol, or ketamine could prove beneficial if subjected to more research. Other options were rejected, and there was controversy about the usefulness of topical preparations. DISCUSSION: For patients who do not respond to standard NP treatments, some other viable pharmacological options can be attempted before advancing to other therapeutic stages. This may help patients who are reluctant to or have some contraindication for interventional therapies.

Update on Interventional Management of Neuropathic Pain: A Delphi Consensus of the Spanish Pain Society Neuropathic Pain Task Force.

Background and Objectives: Interventional management of neuropathic pain (NP) is available to the patients who do not obtain satisfactory pain relief with pharmacotherapy. Evidence supporting this is sparse and fragmented. We attempted to summarize and critically appraise the existing data to identify strategies that yield the greatest benefit, guide clinicians, and identify areas that merit further investigation. Material and Methods: A two-round Delphi survey that involved pain clinic specialists with experience in the research and management of NP was done over an ad hoc 26-item questionnaire made by the authors. Consensus on each statement was defined as either at least 80% endorsement or rejection after the 2nd round. Results: Thirty-five and 29 panelists participated in the 1st and 2nd round, respectively. Consensus was reached in 20 out of 26 statements. There is sufficient basis to treat postherpetic neuralgias and complex regional pain syndromes with progressive levels of invasiveness and failed back surgery syndrome with neuromodulation. Radiculopathies and localized NP can be treated with peripheral blocks, neuromodulation, or pulsed radiofrequency. Non-ablative radiofrequency and non-paresthetic neuromodulation are efficacious and better tolerated than ablative and suprathreshold procedures. Conclusions: A graded approach, from least to most invasive interventions has the potential to improve outcomes in many patients with common refractory NP conditions. Preliminary promising data warrant further research on new indications, and technical advances might enhance the safety and efficacy of current and future therapies.

Safety and cardiovascular effects of multiple-dose administration of aripiprazole and olanzapine in a randomised clinical trial.

OBJECTIVE: To assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment. METHODS: Twenty-four healthy volunteers receiving five daily oral doses of 10 mg ARI and 5 mg OLA in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Blood pressure (BP) and 12-lead electrocardiogram were measured in supine position. AEs were also recorded. RESULTS: ARI decreased diastolic BP on the first day and decreased QTc on the third and fifth day. OLA had a systolic and diastolic BP, heart rate and QTc lowering effect on the first day. Polymorphisms in ADRA2A, COMT, DRD3 and HTR2A genes were significantly associated to these changes. The most frequent adverse drug reactions (ADRs) to ARI were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to OLA. Additionally, HTR2A, HTR2C, DRD2, DRD3, OPRM1, UGT1A1 and CYP1A2 polymorphisms had a role in the development of ADRs. CONCLUSIONS: OLA induced more cardiovascular changes; however, more ADRs were registered to ARI. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects.

Influence of CYP2B6 activity score on the pharmacokinetics and safety of single dose efavirenz in healthy volunteers.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor used as first-line therapy for the treatment of HIV infection. Cytochrome P450 (CYP) CYP2B6 G516T (rs3745274) is a well-known predictor of efavirenz disposition. Dose adjustment based on G516T variant has been shown to be beneficial. However, this variant cannot explain the entire variability of efavirenz pharmacokinetics. In this study, we evaluated the influence of 11 single-nucleotide polymorphisms (SNPs) in CYP2B6, CYP2A6, CYP3A and ABCB1 (ATP-binding cassette sub-family B member 1) on the pharmacokinetics and safety of efavirenz after single oral dose administration to 47 healthy volunteers. We designed and validated a CYP2B6 activity score model based on two CYP2B6 SNPs (G516T and rs4803419) that predicted efavirenz disposition better than G516T alone.

The effects of aripiprazole and olanzapine on pupillary light reflex and its relationship with pharmacogenetics in a randomized multiple-dose trial.

AIMS: Pupillography is a noninvasive and cost-effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics. METHODS: Twenty-four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro-aripiprazole and olanzapine plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes. CONCLUSIONS: In conclusion, aripiprazole and its main metabolite, dehydro-aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.

Histone modifications associated with biological drug response in moderate-to-severe psoriasis.

INTRODUCTION: Epigenetic factors play an important role in psoriasis onset and development. Biological drugs are used to treat moderate-to-severe psoriasis patients resistant to conventional systemic drugs. Although they are safe and effective, some patients do not respond to them. Therefore, it is necessary to find biomarkers that could predict response to these therapies. OBJECTIVE: To find epigenetic biomarkers that could predict response to biological drugs (ustekinumab, secukinumab, adalimumab, ixekizumab). MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 39 psoriasis patients treated with biological therapies before and after drug administration and from 42 healthy subjects. Afterwards, histones were extracted from PBMCs. Four histone modifications (H3 and H4 acetylation, H3K4 and H3K27 methylation) were determined by ELISA. Data were analysed by IBM-SPSS v.23. RESULTS AND CONCLUSIONS: Psoriasis patients presented reduced levels of acetylated H3 and H4 and increased levels of methylated H3K4 compared to controls. Non-significant changes were observed after treatment administration in any of the histone modifications analysed. Nevertheless, significant changes in methylated H3K27 were found between responders and non-responders to biological drugs at 3 months. As 28% of these patients also presented psoriatic arthritis (PsA), the former analysis was repeated in the subsets of patients with or without PsA. In patients without PsA, significant changes in methylated H3K4 were found between responders and non-responders to biological drugs at 3 and 6 months. Although further studies should confirm these results, these findings suggest that H3K27 and H3K4 methylation may contribute to patients' response to biological drugs in psoriasis.

Evaluation of sex-by-formulation interaction in bioequivalence studies of efavirenz tablets.

AIMS: The existence of a sex-by-formulation interaction in bioequivalence studies implies that the bioequivalence results (i.e., the test/reference ratio of the pharmacokinetic parameters) obtained in one sex are not similar to those obtained in the other sex. Therefore, results obtained in studies including only males would not be representative of the results that would have been obtained in females and vice versa. Recently, a sex-by-formulation interaction has been reported in a study for efavirenz tablets. The purpose of this paper is to investigate whether a sex-by-formulation interaction is actually observed in the bioequivalence studies conducted with efavirenz tablets. METHODS: The existence of sex-by-formulation interaction was investigated in the two studies conducted in our centre, where the same test and reference products were investigated in a pilot study with 12 subjects and a pivotal study with 36 subjects. RESULTS: In the pilot study, the point estimates for the test/reference ratio of geometrics means of Cmax in females and males were more than 20% different (95.42% vs.79.38%, i.e., 120.21%), but in a subsequent pivotal study the difference was less than 2% (111.14% vs. 109.98%, i.e., 101.66%). CONCLUSIONS: A sex-by-formulation interaction is suggested in the study with a small sample size, but it disappears when the study is repeated with a larger sample size. In conclusion, the analysis of subgroups should be conducted with caution when the size of the subgroups is not powered to show bioequivalence. There seems to be no reason to require bioequivalence studies for efavirenz in both sexes.

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers.

AIMS: The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. METHODS: The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. RESULTS: Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. CONCLUSIONS: Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HR.

Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers.

OBJECTIVE: To identify genetic markers capable of predicting the pharmacokinetics, pharmacodynamics, and adverse effects of risperidone. METHODS: Genotyping was performed in 70 healthy volunteers receiving a single 1mg oral dose of risperidone. Risperidone and hydroxyrisperidone plasma levels were measured using high-performance liquid chromatography combined with tandem mass spectrometry.Prolactin concentration was quantified by direct chemiluminescence. RESULTS: Poor CYP2D6 metabolizers showed higher risperidone Cmax, area under the curve (AUC), and t1/2, as well as lower clearance. They also showed lower Cmax and AUC and higher t1/2 for hydroxyrisperidone. Furthermore, individuals with a mutant VKORC1 genotype had a lower risperidone AUC and t1/2 and higher clearance. The hydroxyrisperidone AUC was lower in individuals with the COMT mutant genotype. Risperidone increased prolactin levels (iAUC and iCmax), which were higher in women than in men. The most frequent reactions were somnolence (47.1%), headache (21.4%), and dizziness (17.1%). Women had neurological effects and headache more frequently than men. The incidence of headache was associated with polymorphisms in the AGTR1 and NAT2; neurological effects were associated with CYP2C19. CONCLUSIONS: Differences in the pharmacokinetics of risperidone are due to polymorphisms in CYP2D6, COMT, and VKORC1. Differences in adverse reactions can be explained by gender and polymorphisms in CYP2C19, AGTR1, and NAT2.

Use of Exposure Data to Establish Causality in Drug-Adverse Event Relationships: An Example with Desvenlafaxine.

Causality algorithms help establish relationships between drug use and adverse event (AE) occurrence. High drug exposure leads to a higher likelihood of an AE being classified as an adverse drug reaction (ADR). However, there is a knowledge gap regarding what concentrations are predictive of ADRs, as this has not been systematically studied. In this work, the Spanish Pharmacovigilance System (SEFV) algorithm was used to define the relationship between the AE occurrence and drug administration in 178 healthy volunteers participating in five desvenlafaxine single-dose clinical trials, a selective serotonin and norepinephrine reuptake inhibitor that may cause dizziness, headache, nausea, dry mouth, constipation and hyperhidrosis. Eighty-three subjects presented 172 AEs that were classified as possible (101), conditional (31), unrelated (24) and probable (16). AUC∞ and Cmax were significantly higher in volunteers with vs. without ADRs (5981.24 ng·h/mL and 239.06 ng/mL and 4770.84 ng·h/mL and 200.69 ng/mL, respectively). Six of 19 subjects with conditional AEs with an SEFV score of 3 points presented an AUC∞ ≥ 6500 ng·h/mL or a Cmax ≥ 300 ng/mL (i.e., above percentile 75) and were summed one point on their SEFV score and classified as "possible" (4 points), improving the capacity of ADR detection.

Pain in Long-Term Cancer Survivors: Prevalence and Impact in a Cohort Composed Mostly of Breast Cancer Survivors.

Cancer survival is becoming more common which means that there is now a growing population of cancer survivors, in whom pain may be common. However, its prevalence has hardly been addressed systematically. We aimed to assess the prevalence and explore the pathophysiology and impact of pain on health outcomes in cancer survivors. We conducted a retrospective-prospective cohort study in cancer-free patients diagnosed with cancer at least five years before the study start date. We used multivariable regression to establish the association of patients' cancer characteristics with pain, and then the association of patients' pain features with health outcomes and related symptoms. Between March and July 2021, 278 long-term cancer survivors were evaluated. Almost half of them (130/278, 46.8%) had pain, of whom 58.9% had a probable neuropathic component, but only 18 (13.8%) were taking specific drugs for neuropathic pain. A history of surgery-related pain syndrome in breast cancer patients was more than twice as frequent in the pain cohort. Post-chemotherapy and post-radiotherapy pain syndromes were uncommon. Pain was associated with lower QoL, emotional functioning, professional performance, and disability scores. Pain is a frequent health determinant in cancer survivors. Referral to specialised pain services may be a reasonable move in some cases.

Genetic variation in UGT1A1 is not associated with altered liver biochemical parameters in healthy volunteers participating in bioequivalence trials.

Introduction: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant. GS is a benign genetic disorder characterized by elevated bilirubin levels, the primary cause of which is the presence of polymorphisms in UGT1A1 gene. In this work, subjects with UGT1A1 intermediate (IM) or poor (PM) metabolizer genotype-informed phenotypes were investigated to determine whether they have a higher incidence of liver disease or other biochemical parameters. Methods: The study population comprised 773 healthy volunteers who underwent biochemical analysis at baseline and at the end of the study which were genotyped for UGT1A1*80 (rs887829), as an indicator of UGT1A1*80+*28 (rs887829 and rs3064744), and UGT1A1*6 (rs4148323). Results: Bilirubin levels were higher in subjects IMs and PMs compared to normal metabolizers (NMs). Decreased uric acid levels was observed in PMs compared to NMs. No associations were observed in liver enzyme levels according to UGT1A1 phenotype. Discussion: Considering that there is no hepatic toxicity in subjects with UGT1A1 IM or PM phenotype, who are more likely to develop GS, this study suggests that they could be included in bioequivalence clinical trials as their biochemical parameters are not affected outside normal ranges.

Impact of CYP2D6 and CYP2B6 phenotypes on the response to tramadol in patients with acute post-surgical pain.

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized ß coefficients = 0.386 and 0.346, R2 = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized ß coefficient = 0.224, R2 = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response.

Evaluation of the relationship between sex, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers.

Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C(max) than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects.

OBJECTIVE: The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug-metabolizing enzymes, transporters, or receptors. The aim of this study was to identify genetic markers predictive of pharmacokinetics, pharmacodynamics, and adverse effects of olanzapine. METHODS: Sixty-three healthy volunteers receiving a single 5-mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine. All genetic variants were analyzed by PharmaChip, but DRD2 Taq1A polymorphism was determined by real-time polymerase chain reaction. Olanzapine was measured using high-performance liquid chromatography combined with tandem mass spectrometry. The relationship of gender and polymorphisms with olanzapine pharmacokinetics, the change in prolactin levels, and the incidence of adverse effects were evaluated by multiple regression analysis. RESULTS: The pharmacokinetics of olanzapine was influenced by polymorphisms in CYP3A5, GSTM3, and GRIN2B. Prolactin levels were affected by gender and polymorphisms in DRD2 and 5-HTR2A. Polymorphisms in CYP2C9, TPMT, UGT1A1, MDR1, and 5-HTR2A were related to some adverse effects of olanzapine. CONCLUSIONS: Several polymorphisms can explain differences in the pharmacokinetics, pharmacodynamics, and safety of olanzapine in healthy subjects. Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established.

Alternative Pharmacokinetic Metrics in Single-Dose Studies to Ensure Bioequivalence of Prolonged-Release Products at Steady State-A Case Study.

(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, Cτ, partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for Cmax, AUC0-t and AUC0-inf, in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (Cmax, AUC0-t and AUC0-inf) and additional (Cτ, pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC0-τ, Cmax,ss, and Cτ,ss) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration-time curves precluded to show equivalence for Cτ,ss in the simulated study at steady state. This failure to show equivalence at steady state was predicted by Cτ, pAUCs and HVD in the single-dose study. Cτ was the most sensitive metric for detecting the different shape, with a lower intra-subject variability than HVD; (4) Conclusions: conventional PK metrics for single-dose studies (Cmax, AUC0-t and AUC0-inf) are not enough to guarantee bioequivalence at steady state for prolonged-release products.

Genetic Variation in CYP2D6 and SLC22A1 Affects Amlodipine Pharmacokinetics and Safety.

Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t1/2) (univariate p-value (puv) = 0.039, multivariate p-value (pmv) = 0.013, ß = -5.31, R2 = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). SLC22A1 rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC72/DW) (puv = 0.025; pmv = 0.026, ß = 578.90, R2 = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for CYP2D6, SLC22A1 and CYP3A4. In addition to the previous associations, CYP2D6 UMs showed a lower AUC72/DW (puv = 0.046, pmv = 0.049, ß = -68.80, R2 = 0.073) compared to NMs, IMs and PMs and the SLC22A1 rs34059508 G/A genotype was associated with thoracic pain (puv = 0.038) and dizziness (puv = 0.038, pmv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and CYP2D6 and SLC22A1. Further research is needed to gather more evidence before its application in clinical practice.

Identification of Transporter Polymorphisms Influencing Metformin Pharmacokinetics in Healthy Volunteers.

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4, influenced AUC. The maximum concentration was affected by age and SLC22A1, but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2, and SLC22A4. The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3. The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3. Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1, SLC2A2, SLC22A2, or SLC47A1. Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.

NAT2 phenotype alters pharmacokinetics of rivaroxaban in healthy volunteers.

Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower tmax (2.21 h vs 2.88 h, ß = 1.19, R2 =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC∞ corrected by dose/weight (AUC∞/DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, ß = 0.154, R2 =0.250, p = 0.044), higher Cmax/DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, ß = 0.245, R2 =0.320, p = 0.002), and lower tmax (2.63 vs 3.19 and 4.15 h, ß = -0.346, R2 =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC∞ and Cmax. Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance.