Differences In Drug Dose Research Articles

Plasma trough concentrations of antihypertensive drugs for the assessment of treatment adherence: a meta-analysis

Abstract Background Non-adherence to antihypertensive drugs is an important behavioral contributor to poor blood pressure control and is associated with increased risk of cardiovascular disease, hospitalization and increased healthcare costs. Biochemical drug screening in plasma is an accurate method for the detection of non-adherence. When performed qualitatively (present/not present) this method may lead to overestimation of adherence to drugs with long half-lives. Detection of non-adherence may be improved by performing it quantitatively (measurement of exact concentrations) making use of reliable, drug-specific cut-off values based on exposure parameters in plasma. Purpose To perform a literature review and meta-analysis of pharmacokinetic studies to determine plasma population trough concentrations of three frequently prescribed antihypertensive drugs with different pharmacological properties; amlodipine, hydrochlorothiazide and valsartan. These population trough concentrations could possibly be used as drug-specific cut-off values for the diagnosis of (non-)adherence. Methods PubMed was searched for pharmacokinetic studies regarding amlodipine, hydrochlorothiazide and valsartan up to December 2019. Eligible studies reported steady-state mean trough concentration estimates and their variance measured in healthy subjects or in patients with hypertension without hepatic or renal failure. Pooled trough concentrations were estimated using a DerSimonian and Laird random-effect approach. To take dependency between mean trough concentrations into account a multilevel meta-analysis was performed. Meta-regression was used to explore sources of heterogeneity identified by the I2 statistic. Results The literature search identified 1154 potentially relevant articles of which 44 were eligible for inclusion; 23 for amlodipine, 10 for hydrochlorothiazide and 11 for valsartan. The overall pooled mean trough concentration estimate was 9.3 ng/ml (95% confidence interval: 8.4–10.2) for amlodipine, 29.4 ng/ml (24.4–43.3) for hydrochlorothiazide and 355.4 ng/ml (294.1–416.6) for valsartan (figure 1A-C). Substantial heterogeneity was present for all three pooled estimates (I2 >90%). Based on meta-regression 33.3%, 20.3% and 8.2% of the heterogeneity between the studies can be explained by differences in dose for amlodipine, hydrochlorothiazide and valsartan, respectively. Conclusions Plasma trough concentrations of amlodipine, hydrochlorothiazide and valsartan are highly heterogeneous over the different study populations. This heterogeneity is caused, at least in part, by differences in drug dose. Use of the pooled trough concentration mean estimate as a cut-off in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence and should therefore be implemented with caution. Future research might focus on combining drug specific pharmacokinetics with individual patient characteristics to predict personalized trough concentrations. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): UMC Utrecht

Impact of sex-specific target dose in chronic heart failure patients with reduced ejection fraction.

A recent study suggested that women with heart failure and heart failure reduced ejection fraction might hypothetically need lower doses of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers ( = renin-angiotensin-system inhibitors) and β-blockers than men to achieve the best outcome. We assessed the current medical treatment of heart failure reduced ejection fraction in men and women in a large contemporary cohort and address the hypothetical impact of changing treatment levels in women. This analysis is part of a large contemporary quality of heart failure care project which includes 5320 (64%) men and 3003 (36%) women with heart failure reduced ejection fraction. Detailed information on heart failure therapy prescription and dosage were collected. Women less often received renin-angiotensin-system inhibitors (79% vs 83%, p < 0.01), but more often β-blockers (82% vs 79%, p < 0.01) than men. Differences in guideline-recommended target doses between sexes were relatively small. Implementing a hypothetical sex-specific dosing schedule (at 50% of the current recommended dose in the European Society of Cardiology guidelines in women only) would lead to significantly higher levels of women receiving appropriate dosing (β-blocker 87% vs 54%, p < 0.01; renin-angiotensin-system inhibitor 96% vs 75%, p < 0.01). Most interestingly, the total number of women with >100% of the new hypothetical target dose would be 24% for β-blockers and 52% for renin-angiotensin-system inhibitors, which can be considered as relatively overdosed. In this large contemporary heart failure registry, there were significant but relatively small differences in drug dose between men and women with heart failure reduced ejection fraction. Implementation of the hypothetical sex-specific target dosing schedule would lead to considerably more women adequately treated. In contrast, we identified a group of women who might have been relatively overdosed with increased risk of side-effects and intolerance.

Simultaneous determination of cytosine arabinoside and its metabolite uracil arabinoside in human plasma by LC-MS/MS: Application to pharmacokinetics-pharmacogenetics pilot study in AML patients

Purine analogs like aracytine (AraC) are a mainstay for treating acute myeloid leukemia (AML). There are marked differences in drug dosing and scheduling depending on the protocols when treating AML patients with AraC. Large inter-patient pharmacokinetics variability has been reported, and genetic polymorphisms affecting cytidine deaminase (CDA), the liver enzyme responsible for the conversion of Ara-C to inactive uracil arabinoside (AraU) could be a culprit for either life-threatening toxicities or poor efficacy related to substantial changes in plasma exposure levels among patients. The quantitative determination of Ara-C in plasma is challenging due the required sensitivity because of the short half-life of this drug (i.e., <10 min) and the metabolic instability in biological matrix upon sampling possibly resulting in erratic values. We developed and validated a liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) for the simultaneous determination of Ara-C and Ara-U metabolite in human plasma. After simple and rapid precipitation, analytes were successfully separated and quantitated over a 1–500 ng/ml range for Ara-C and 250–7500 ng/ml range for AraU. The performance and reliability of this method was tested as part of an investigational study in AML patients treated with low dose cytarabine and confirmed marked differences in drug exposure levels and metabolic ratio, depending on the CDA status of the patients. Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in AML patients with respect to their CDA phenotypes.

Current Therapy of Inflammatory Bowel Disease in Children

Ulcerative colitis (UC) and Crohn disease (CD) are chronic intestinal inflammatory diseases that can present as bloody diarrhea, abdominal pain, and malnutrition. Collectively, these disorders are referred to as inflammatory bowel disease (IBD). All patients with IBD share a common pathophysiology. However, there are a number of developmental, psychosocial, and physiologic issues that are unique to the approximate, equals 20% of patients that present during childhood or adolescence. These include the possibility of disease-induced delays in linear growth or physical development, differences in drug dosing, and the changes in social and cognitive development that occur as children move from school-age years into adolescence and early adulthood. Gastroenterologists caring for these children must therefore develop an optimal regimen of pharmacologic therapies, nutritional management, psychologic support, and properly timed surgery (when necessary) that will maintain disease remission, minimize disease and drug-induced adverse effects, and optimize growth and development. This article reviews current approaches to the management of patients with UC and CD and highlights issues specific to the treatment of children with IBD. The principal medical therapies used to induce disease remission in patients with UC are aminosalicylates (for mild disease), corticosteroids (for moderate disease), and cyclosporine (ciclosporin) (for severe disease). If a patient responds to the induction regimen, maintenance therapies that are used to prevent disease relapse include aminosalicylates, mercaptopurine, and azathioprine. Colectomy with creation of an ileal pouch anal anastomosis (J pouch) has become the standard of care for patients with severe or refractory colitis and results in an improved quality of life in most patients. Therefore, the risks associated with using increasingly potent immunosuppressant agents must be balanced in each case against a patient's desire to retain their colon and avoid a temporary or potentially permanent ileostomy. Decisions about drug therapy in the management of patients with CD are more complex and depend on both the location (e.g. gastroduodenal vs small intestinal vs colonic), as well as the behavior of the disease (inflammatory/mucosal vs stricturing vs perforating) in a given patient. Induction therapies for CD typically include aminosalicylates and antibiotics (for mild mucosal disease), nutritional therapy (including elemental or polymeric formulas), corticosteroids (for moderate disease), and infliximab (for corticosteroid-resistant or fistulizing disease). Aminosalicylates, mercaptopurine, azathioprine, methotrexate, and infliximab can be used as maintenance therapies. Because surgical treatment of CD is not curative, it is typically reserved for those patients either with persistent symptoms and disease limited to a small section of the intestine (e.g. the terminal ileum and cecum) or for the management of complications of the disease including stricture or abdominal abscess. When surgery is necessary, maintenance medications administered postoperatively will postpone recurrence. Patients with UC and CD are at risk for the development of micronutrient deficiencies (including folate, iron, and vitamin D deficiencies) and require close nutritional monitoring. In addition, patients with UC and CD involving the colon are at increased risk of developing colon cancer, and should be enrolled into a colonoscopy surveillance program after 8-10 years of disease duration.

Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy

The antiproteinuric effect of angiotensin converting enzyme (ACE) inhibition in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy varies considerably. Therefore, we tested the potential role of an insertion (I)/deletion (D) polymorphism of the ACE gene on this early antiproteinuric responsiveness in an observational follow-up study. Sixty (II, N = 13; ID, N = 26 and DD, N = 21) young hypertensive IDDM patients suffering from diabetic nephropathy were investigated during three months before and for the initial six month period during ACE inhibition [captopril 44 (SD 22) mg/24 hr, no differences in drug dose between groups]. Blood pressure (MABP) and albuminuria (ELISA) were measured three (1 to 6) times before and three (1 to 13) times during ACE inhibition. At baseline the groups (II/ID/DD) had comparable (1) mean arterial blood pressure (MABP mm Hg) of 113 +/- 10/108 +/- 9/114 +/- 8, (2) albuminuria (geometric mean with 95% CI) 1394 (747 to 2608)/1176 (844 to 1797) and 1261 (827 to 2017) mg/24 hr, and (3) serum creatinine (geometric mean with 95% CI), 80 (68 to 93)/85 (76 to 97)/103 (85 to 119) mumol/liter, respectively. Angiotensin converting enzyme inhibition induced a significant reduction in MABP, albuminuria and kidney function in all three groups (II/ID/DD; P < 0.05): (1) MABP (mean +/- SD) 12 +/- 7/5 +/- 7/8 +/- 9 mm Hg (ANOVA, P = 0.02); (2) albuminuria [mean (95% CI)] 61 (34 to 77)/22 (3 to 37)/31 (13 to 46) %, (ANOVA, P < 0.01); and (3) increasing serum creatinine [mean (95% CI)] 8 (4 to 12)/9 (3 to 16)/8 (0 to 16) % (ANOVA, NS), respectively. Adjusting for differences in reduction in MABP did not change the association between decrease in albuminuria and ACE/ID genotypes (P < 0.01). A multiple linear regression analysis revealed that the ACE/ID polymorphism, albuminuria and MABP at baseline independently influenced the decline in albuminuria after initiation of ACE inhibition (R2 = 0.21, P < 0.01). A significant association between changes in MABP and albuminuria was demonstrated (R2 = 0.16, P < 0.01). Our data show that hypertensive albuminuric IDDM patients with the II genotype are particularly susceptible to commonly advocated renoprotective treatment.

Further Studies Demonstrating an Increased Erythemal Threshold Following Oral Methoxsalen

The use of methoxsalen or 8-methoxypsoralen to augment the normal skin response to ultraviolet light has been intensively studied in recent years. An extensive symposium on psoralens and radiant energy was published in a supplement to this journal in February, 1959 (1). Included in that issue was a report by Imbrie,et al. on increased erythemal threshold five weeks after a single exposure to sunlight and ingestion of 30 mg. of methoxsalen (2). In an experimental group of eight young women, it was shown that nearly twice as much ultraviolet exposure was necessary to produce an erythema on the methoxsalen treated skin as was needed to produce a comparable amount on the control area. However, these results were much more impressive than were those obtained on men receiving 20 mg. of methoxsalen with repetitive solar exposures in Idaho and Arizona (3). Because of differences in drug dose, geographic location and sex, further experiments were required to explain the differences. This report concerns a larger series of males to reaffirm the magnitude of the protective effect and to investigate possible sex differences in response to this drug.