Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials.

BACKGROUND: A recent study of older men participating in the Testosterone Trials (TTrials) defined a clinically meaningful change in the Psychosexual Daily Questionnaire (PDQ) question 4 in hypogonadal men age ≥65 years. This study defines clinically meaningful change in the same population for sexual desire assessed by PDQ question 1. AIM: To determine a clinically meaningful change in the answers to question 1 of the PDQ in hypogonadal older men. METHODS: Participants in the Sexual Function Trial of the TTrials were randomly divided into a training and test set. Anchor-based methods, including regression analysis, receiver operating characteristic curves, and empirical cumulative distribution functions, were used to determine a clinically meaningful change on question 1 in the training set, and the selected threshold was evaluated in the test set for an effect of testosterone treatment. RESULTS: A clinically meaningful increase in question 1 of the PDQ was determined to be ≥0.7 points. CLINICAL IMPLICATIONS: Question 1 of the PDQ can be used to assess sexual desire in response to testosterone treatment. STRENGTHS & LIMITATIONS: Data were obtained from a single large study of older hypogonadal men. CONCLUSION: Clinically meaningful improvement of sexual desire is a change of ≥0.7 in the score of question 1 of the PDQ. Stephens-Shields AJ, Wang C, Preston P, et al. Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials. J Sex Med 2019;16:951-953.

Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials.

BACKGROUND: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function. AIM: To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains. METHODS: Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set. OUTCOMES: Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials. RESULTS: Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men. CLINICAL IMPLICATIONS: The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T. STRENGTHS & LIMITATIONS: Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity. CONCLUSION: Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997-1009.

Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial.

BACKGROUND: High levels of circulating fibroblast growth factor 23 (FGF23) are associated with chronic kidney disease (CKD) progression and high mortality. In the Phosphate Reduction Evaluation of FGF23 in Early CKD Treatment (PREFECT) study, we assessed the effect of reducing intestinal phosphate absorption using lanthanum carbonate on FGF23 levels in normophosphatemic patients with CKD stage 3. METHODS: Thirty-five individuals were randomized to lanthanum carbonate 3000 mg/day (n=23) or placebo (n=12) for 12 weeks. Levels of intact FGF23 (iFGF23), C-terminal FGF23, serum and urinary phosphate and calcium, intact parathyroid hormone and 1,25-dihydroxyvitamin D were assessed. RESULTS: The median age was 65 years in the lanthanum group and 73 years in the placebo group; 58.8% and 41.7% were men, respectively. No significant difference was seen in mean iFGF23 between groups at week 12. There was, however, a transient reduction from baseline in iFGF23 in the lanthanum group at week 1, from 70.5 pg/ml to 51.9 pg/ml, which was not seen in the placebo group; this between-group difference in percentage change from baseline was significant in post hoc analyses (p=0.0102). Urinary phosphate decreased after 1 week of lanthanum treatment and remained low at week 12. CONCLUSIONS: Reducing intestinal phosphate absorption with lanthanum carbonate did not lead to sustained reductions in iFGF23 in patients with CKD stage 3, although phosphaturia decreased. This suggests that factors other than phosphate burden may be responsible for driving increases in circulating FGF23 in patients with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01128179, 20 May 2010.

Clinically Important Differences for Mobility Measures Derived from the Testosterone Trials.

BACKGROUND/OBJECTIVES: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men. DESIGN: Longitudinal, multisite placebo-controlled trial. SETTING/PARTICIPANTS: Men enrolled in the Testosterone Trials who had self-reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone- and placebo-allocated participants were combined for this study. RESULTS: Mean changes from baseline, adjusting for time-in-intervention and site, were 29.6, 13.2, 12.5, -2.4, and -32.6 m for 6MWD, and 15.4, 7.2, 2.1, -3.4, and -7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0-29.6 m for 6MWD, and 5.0-15.2 points for PF10. CONCLUSION: CID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility-limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function.

Biomarkers and Noncalcified Coronary Artery Plaque Progression in Older Men Treated With Testosterone.

OBJECTIVE: Recent results from the Cardiovascular Trial of the Testosterone Trials showed that testosterone treatment of older men with low testosterone was associated with greater progression of noncalcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the Testosterone Trial. METHODS: The Cardiovascular part of the trial included 170 men aged 65 years or older with low testosterone. Participants received testosterone gel or placebo gel for 12 months. The primary outcome was change in NCP volume from baseline to 12 months, as determined by coronary computed tomography angiography (CCTA). We assayed several markers of cardiovascular risk and analyzed each marker individually in a model as predictive variables and change in NCP as the dependent variable. RESULTS: Of 170 enrollees, 138 (73 testosterone, 65 placebo) completed the study and were available for the primary analysis. Of 10 markers evaluated, none showed a significant association with the change in NCP volume, but a significant interaction between treatment assignment and waist-hip ratio (WHR) (P = 0.0014) indicated that this variable impacted the testosterone effect on NCP volume. The statistical model indicated that for every 0.1 change in the WHR, the testosterone-induced 12-month change in NCP volume increased by 26.96 mm3 (95% confidence interval, 7.72-46.20). CONCLUSION: Among older men with low testosterone treated for 1 year, greater WHR was associated with greater NCP progression, as measured by CCTA. Other biomarkers and anthropometric measures did not show statistically significant association with plaque progression.

Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial.

CONTEXT: Prostate-specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated. DESIGN: Double-blinded, placebo-controlled trial. SETTING: Twelve US academic medical centers. PARTICIPANTS: Seven hundred ninety hypogonadal men ≥65 years of age with average testosterone levels ≤275 ng/dL. Men at high risk for prostate cancer were excluded. INTERVENTIONS: Testosterone or placebo gel for 12 months. MAIN OUTCOMES: Percentile changes in PSA during testosterone treatment of 12 months. RESULTS: Testosterone treatment that increased testosterone levels from 232 ± 63 ng/dL to midnormal was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean ± SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥1.7 ng/mL and 2.5% of men had an increase of ≥3.4 ng/mL. A confirmed absolute PSA >4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer; two were Gleason 8. CONCLUSIONS: When hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥1.7 ng/mL, and 2.5% had an increase ≥3.4 ng/mL.

Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials.

BACKGROUND: The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. METHODS: The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov, number NCT00799617. FINDINGS: The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2-15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5-6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5-21·9; p=0·0004) and PF10 (4·9, 2·2-7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0-14·1; p=0·0237) and PF10 (3·6, 1·3-5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35-3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61-5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall). INTERPRETATION: Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations. FUNDING: US National Institute on Aging and AbbVie.

The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials.

Context: Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective: To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Design: Double-blind, placebo-controlled trial. Setting: Twelve academic medical centers in the United States. Participants: In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Intervention: Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcome Measures: Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Results: Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, -1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo. Conclusions and Relevance: Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes.

Effects of Altering Trunk Position during Landings on Patellar Tendon Force and Pain.

PURPOSE: This study aimed to verify the immediate effects of altering sagittal plane trunk position during jump landings on lower limb biomechanics, patellar tendon force, and pain of athletes with and without patellar tendinopathy. METHODS: Twenty-one elite male athletes were categorized into three groups: athletes with patellar tendinopathy (TG; n = 7), asymptomatic athletes with patellar tendon abnormalities (n = 7), and asymptomatic athletes without tendon abnormalities (CG; n = 7). A biomechanical evaluation was conducted while the athletes performed drop landings from a bench in a self-selected trunk position (SS). Afterward, the athletes were randomly assigned to land with either a flexed trunk position (FLX) or an extended trunk position (EXT). Variables of interest for this study included sagittal plane peak kinematics, kinetics, patellar tendon force, and pain during the landing tasks. RESULTS: Peak patellar tendon force, knee extensor moment, and knee pain decreased in the FLX landing compared with the SS landing, regardless of group. In addition, peak patellar tendon force, knee extensor moment, and vertical ground reaction force were smaller in the FLX landing compared with the EXT landing. The TG had smaller peak ankle dorsiflexion compared with the CG during jump landings, regardless of trunk position. CONCLUSIONS: Landing with greater trunk flexion decreased patellar tendon force in elite jumping athletes. An immediate decrease in knee pain was also observed in symptomatic athletes with a more flexed trunk position during landing. Increasing trunk flexion during landing might be an important strategy to reduce tendon overload in jumping athletes.

Iron-deficiency anaemia caused by an enterolith-filled jejunal duplication cyst.

Enterogenous duplication cysts are rare, but recognised, developmental anomalies. Duplications in the midgut are the commonest of these rare anomalies with a high proportion of them being found in the jejunum. Enterolith formation within these duplication cysts is uncommon as is heterotopic mucosa giving rise to peptic ulceration. Mode of presentation depends on whether symptoms due to mass effect or gastrointestinal bleeding predominate. We present a case of iron-deficiency anaemia caused by an enterolith-filled jejunal duplication cyst diagnosed at laparotomy and treated by surgical excision and small bowel resection.

Cost-minimization analysis of lanthanum carbonate versus sevelamer hydrochloride in US patients with end-stage renal disease.

PURPOSE: Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used in the clinical management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to assess the cost-effectiveness of LC monotherapy compared with SH monotherapy in US patients with ESRD in a clinical practice setting. METHODS: This was a post hoc assessment of phosphate binder costs among US patients with ESRD who converted from SH to LC monotherapy in a previously published, 16-week, Phase IV, real-world study. Calculations of drug costs used both average wholesale price (AWP) and wholesale acquisition cost (WAC). FINDINGS: There were 953 patients with available baseline SH dose data; 950 also had a recorded LC dose >0 mg at baseline, and 691 had dose data available for both SH at baseline and LC at week 16 (post hoc analysis population). Baseline demographic characteristics were similar in excluded patients and the post hoc analysis population. Mean (SD) serum phosphate levels were 5.91 (1.66) mg/dL at baseline and 5.93 (1.85) mg/dL after conversion to LC monotherapy for 16 weeks. Mean AWP costs were US$35.72 (16.89) per day at baseline and US$24.69 (8.28) per day at week 16, yielding an overall mean cost change (defined as LC cost - SH cost) of -US$11.03 (16.37) per day in favor of LC. The overall mean WAC cost change was -US$9.17 (13.64) per day. Within baseline SH dose subgroups 2400 to 4800, >4800 to 7200, >7200 to 9600, and >9600 mg/d, the mean AWP cost change ranged from US$2.78 (9.26) per day in favor of SH for the 2400- to 4800-mg/d subgroup to -US$33.15 (12.58) per day in favor of LC for the >9600-mg/d subgroup. Mean WAC cost changes showed a similar trend, ranging from US$2.33 (7.72) per day to -US$27.59 (10.48) per day. Linear regression analyses revealed that the inflection SH doses corresponding to a mean cost change of zero were 4905 mg/d (AWP) and 4908 mg/d (WAC). For the 455 (66%) patients in the post hoc analysis population who had baseline SH doses at least as high (≥ 5600 mg/d) as these point estimates, the mean SH:LC tablet ratio was ≥ 3.7, indicating a mean reduction in the tablet burden after conversion to LC of ≥ 73%. IMPLICATIONS: This real-world assessment of comparative phosphate binder drug costs between SH and LC among US patients with ESRD indicates that average cost savings with LC use increased with increasing SH doses. Conversion to LC from SH ≥ 5600 mg/d reduced drug costs and tablet burden while maintaining serum phosphate levels.

Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials.

BACKGROUND: MMX(®) mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections. AIM: To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies. METHODS: In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1-4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1-3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1-3 and once on day 4 (N=44). RESULTS: MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) fell within the predefined equivalence range (0.80-1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild. CONCLUSION: MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics. CLINICALTRIALSGOV IDENTIFIERS: NCT01442688, NCT01402947, NCT01418365, and NCT01469637.

The real-world dose-relativity of sevelamer hydrochloride and lanthanum carbonate monotherapy in patients with end-stage renal disease.

INTRODUCTION: Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to evaluate the real-world dose-relativity between SH and LC monotherapy in US patients with ESRD. METHODS: This was a post hoc analysis of a 16-week, real-world study (Vemuri et al. in BMC Nephrol 12:49, 2011) of the efficacy of conversion to LC monotherapy from other phosphate binders. The SH:LC dose-relativity ratio, based on the mean daily dose, was calculated in the subset of patients from the Vemuri study who converted from SH to LC monotherapy and had available SH and LC dose data. RESULTS: A total of 950 patients converted from SH to LC monotherapy and had recorded dose data. The post hoc analysis population comprised 691 patients with available dose data for both SH at baseline and LC at week 16. The mean (SD) serum phosphate level at baseline was 5.91 (1.66) mg/dL. After conversion to LC monotherapy for 16 weeks, the mean (SD) serum phosphate level was 5.93 (1.85) mg/dL. The mean (SD) daily baseline SH dose was 7,703 (3,642) mg and the mean (SD) daily LC dose at week 16 was 2,800 (939) mg (9.6 versus 2.8 tablets, respectively; P < 0.0001), resulting in a SH:LC dose-relativity ratio of 2.8. The median individual patient SH:LC dose-relativity ratio was 2.6 (95% CI 2.6-2.8). Across baseline SH dose subgroups (2,400-4,800, >4,800-7,200, >7,200-9,600, and >9,600 mg/day), the mean daily SH dose was 4,051, 7,047, 9,253, and 13,150 mg, respectively. In comparison, the mean daily LC dose was 2,445-3,156 mg. Thus, patients requiring baseline SH doses >7,200 mg/day (41% of the analysis population) had higher SH:LC dose-relativity ratios of 3.1-4.2 (median individual patient ratios 3.1-4.0). CONCLUSION: In this post hoc analysis of real-world dose-relativity, the overall SH:LC dose-relativity ratio was 2.8 (median individual patient ratio 2.6 (95% CI 2.6-2.8). These findings are consistent with the World Health Organization-defined daily dose and previous studies of the relative phosphate binding capacity of the two drugs. Patients requiring SH doses >7,200 mg/day had higher SH:LC dose-relativities of 3.1-4.2 (median individual patient ratios 3.1-4.0). These findings have implications for the tablet burden and cost-effectiveness of SH and LC in the treatment of hyperphosphatemia.

Pharmacokinetics of coadministered guanfacine extended release and lisdexamfetamine dimesylate.

BACKGROUND: In clinical practice, α2-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug-drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated. OBJECTIVE: The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination. STUDY DESIGN: This was an open-label, randomized, three-period crossover, DDI study. SETTING: The study was conducted in a single clinical research center. PARTICIPANTS: Forty-two healthy adults were randomized in this study. INTERVENTIONS: Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination. MAIN OUTCOME MEASURES: Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80-1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs). RESULTS: Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0-∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90% CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90% CI exceeded the standard range for bioequivalence by 7%. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9% of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3%) and headache (7.5, 4.9, and 7.3%) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX. CONCLUSIONS: In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.

Phyllodes tumour of the prostate posing diagnostic and therapeutic dilemmas.

A rare case of phyllodes tumour of the prostate of which less than 100 cases have been reported in the literature. It has an unclear clinical course and uncertain management options. In an inoperable case such as this, the authors discuss the difficulties faced with its management and the limited, possibly palliative role, of hormonal treatment using luteinising hormone-releasing hormone analogue in managing it over a medium term.