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Results for “Targeted dosing”

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At least 433 records · Page 24Linked to original sources

PubMed2006

Cognitive effects of low-dose topiramate monotherapy in epilepsy patients: A 1-year follow-up.

The present study was conducted to evaluate the long-term effects of low-dose topiramate (TPM) monotherapy on the cognitive function of epilepsy patients. Forty-seven epilepsy patients received TPM, with target doses of 50, 75, and 100 mg/day. Cognitive tests were performed twice, at baseline and 1 year after starting medication. Thirty-six patients completed the follow-up neuropsychological tests. After a year of treatment, 16 patients (44%) complained of cognitive problems. Although it improved seizure frequency and EEG abnormalities, TPM had significantly negative effects on the digit span and verbal fluency tests. These cognitive effects were dose-related and significantly improved after withdrawal from TPM and substitution with older antiepileptic drugs. In conclusion, even at a low dose, TPM has long-term, negative effects on working memory and verbal fluency.

Adolescent↗

PubMed1997

Results of re-irradiation of primary intracranial neoplasms with three-dimensional conformal therapy.

We evaluated the potential of three-dimensional conformal therapy for re-irradiation of selected intracranial neoplasms and reviewed the retreatment of 20 patients at the University of Michigan between May 1988 and August 1991. All patients had previously undergone a full course of external beam radiotherapy (RT) to a median dose of 5,940 cGy (range 5,100-6,500 cGy), including five whole brain treatments. All recurrences were unsuitable for brachytherapy or radiosurgery. Various histologies were retreated, including 14 high-grade gliomas. Median time to re-irradiation was 38 months (range 9 months to 19 years, 6 months). RT was delivered with complex plans designed using fully integrated computed tomography/magnetic resonance imaging (CT/ MRI) tumor volume information, and regions of previous parenchymal treatment were avoided if possible. Composite (initial+retreatment) dose-volume histograms (DVH) of dose to nontarget brain allowed comparison of alternative plans to select beam orientations which minimized normal brain irradiation. Mean target dose of re-irradiation was 3,600 cGy (range 3,060-5,940 cGy). Total cumulative dose ranged from 8,060 to 11,940 cGy. Median survival was 9 months, and 1-year actuarial survival was 26%. After retreatment, 8 of 12 patients (67%) had steroid dose decrement and neurologic improvement at 4-48 months (median duration 14 months). Radiographic regression or stabilization of disease was noted in 11 of 16 patients (68%). Re-irradiation with highly conformal three-dimensional planning provides frequent clinical improvement with acceptable morbidity and should be considered in selected patients with recurrent intracranial neoplasms.

Actuarial Analysis↗

PubMed1999

A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms.

Combined data from double-blind risperidone studies were used to analyse the severity of extrapyramidal symptoms (EPS) associated with treatment in patients with chronic schizophrenia. Factors associated with maximum EPS severity were increasing risperidone dose (< or = 8 mg/day was similar to placebo), lower baseline EPS scores, and longer duration of psychotic symptoms, particularly in older patients. EPS severity was significantly greater in patients receiving haloperidol or other antipsychotics than in those receiving risperidone (4 to 8 mg/day) or placebo. Antiparkinsonian medications were required by significantly fewer patients treated with risperidone (4 to 8 mg/day) than by patients treated with haloperidol or other antipsychotics. Combined efficacy data showed that 4 to 8 mg/day was also the most efficacious dose range; there was no increase in efficacy with doses over 4 mg/day. Based on these data and post-marketing experience, 4 mg/day is an appropriate initial target dose for most patients with schizophrenia. Higher doses may be appropriate for patients with chronic illness, and lower doses may be appropriate for patients with a first psychotic episode or for elderly patients.

Adolescent↗

PubMed2003

Sulfadoxine-pyrimethamine in treatment of malaria in Western Kenya: increasing resistance and underdosing.

Between 1993 and 1999, we monitored the efficacy of sulfadoxine-pyrimethamine in 1175 children aged <24 months receiving 2789 treatments for falciparum malaria in western Kenya using a widely deployed age-based dose regimen: infants, 125 plus 6.25 mg (sulfadoxine plus pyrimethamine); children aged 12 to 23 months; 250 plus 12.5 mg. Cumulative treatment failure by day 7, defined as early clinical failure by day 3 or presence of parasitemia on day 7, increased from 18% in 1993 to 1994 to 22% in 1997 to 1998 (P-trend test = 0.20). Based on body weight, the median dose received was 20 plus 1.00 mg/kg, and 73% of the treatments were given at lower than the recommended target dose of 25 plus 1.25 mg/kg. Underdosing accounted for 26% of cumulative treatment failures. After the dose was increased in 1998 (median, 36 plus 1.8 mg/kg), only 4.2% of patients received less than 25 plus 1.25 mg/kg and there was no association with treatment failure. However, the proportion of cumulative treatment failure continued to increase to 27% by 1999 (P-trend test = 0.03). These results raise concern about the longevity of sulfadoxine-pyrimethamine in these settings. Underdosing may have contributed to the rate at which sulfadoxine-pyrimethamine resistance developed in this area. Treatment guidelines should ensure that adequate doses are given from the initial deployment of antimalarials onward.

Anti-Infective Agents↗

PubMed2006

Dynamic IMRT treatments of sinus region tumors: comparison of Monte Carlo calculations with treatment planning system calculations and ion chamber measurements.

Results are presented comparing Monte Carlo (MC) calculations for dynamic IMRT treatments of tumors in the sinus region with Eclipse treatment planning system dose calculations, and ion chamber measurements. The EGS4nrc MC code, BEAMnrc, was commissioned to simulate a Varian 21Ex Linac for both open and IMRT fields. The accuracy of the simulation for IMRT plans was evaluated using a head phantom by comparing MC, Eclipse, TLD results, and ion chamber in solid water phantom measurements. The MC code was then used to simulate dose distributions for five patients who were treated using dynamic IMRT for tumors in the sinus region. The results were compared with absolute and relative dose distributions calculated using Eclipse (pencil beam, modified-Batho inhomogeneity correction). Absolute dose differences were also compared with ion chamber results. Comparison of the doses calculated on the head phantom using MC, compared with Eclipse, ion chamber, and TLD measurements showed differences of -3.9%, -1.4%, and -2.0%, respectively (MC is colder). Relative dose distributions for the patient plans calculated using MC agreed well with those calculated using Eclipse with respect to targets and critical organs, indicating the modified-Batho correction is adequate. Average agreement for mean absolute target doses between MC and Eclipse was -3.0 +/-; 2.3% (1 s.d.). Agreement between ion chamber and Eclipse for these patients was -2.2 +/- 1.9%, compared with 0.2 +/- 2.0% for all head and neck IMRT patients. When Eclipse doses were corrected based on ion chamber results, agreement between MC and Eclipse was -0.7 +/- 2.0%, indicating a small systematic uncertainty in the doses calculated using the treatment planning system for this subset of patients.

Head and Neck Neoplasms↗

PubMed2003

Titration of beta-blockers in heart failure. How to maximize benefit while minimizing adverse events.

Data from large clinical trials indicate that beta-blocker therapy can be successfully initiated and adjusted upward in most patients with stable chronic heart failure who already take standard heart failure therapy. Such therapy typically includes ACE inhibitors, diuretics, and digoxin. With optimal titration and maintenance strategies, beta-blockers are effective and well tolerated in these patients. It is recommened that all patients with clinically stable mild to moderate chronic heart failure (NYHA class II or III), no contraindications to beta-blocker use, and an LVEF less than 40% should be treated with beta-blockers. Based on the results of recent clinical trials on heart failure, beta-blocker therapy should be initiated at a low dose and slowly tirtrated upward as tolerated. A patient's heart failure should be stable for at least 2 weeks before the dose is adjusted upward. Slow titration facilitates maximal tolerability. In primary care practice, physicians should apply titration strategies and target dosed that have been demonstrated to reduce morbidity and mortality in clinical trials. Although worsening heart failure or other adverse events occur in a minority of patients who take beta-blockers, these effects can be managed by adjusting the dose of ACE inhibitor or diuretic, or both, or by temporarily withholding the beta-clocker. Currently, professional treatment guidelines recommend beta-blocker therapy in combination with ACE inhibitors an diuretics as the standard of care in the treatment of heart failure.

Adrenergic beta-Antagonists↗

PubMed2003

Risk models for neutropenia in patients with breast cancer.

Breast cancer is the most common noncutaneous malignancy in women in industrialized countries. Chemotherapy prolongs survival in patients with early-stage breast cancer, and maintaining the chemotherapy dose intensity is crucial for increasing overall survival. Many patients are, however, treated with less than the standard dose intensity because of neutropenia and its complications. Prophylactic colony-stimulating factor (CSF) reduces the incidence and duration of neutropenia, facilitating the delivery of the planned chemotherapy doses. Targeting CSF to only at-risk patients is cost-effective, and predictive models are being investigated and developed to make it possible for clinicians to identify patients who are at highest risk for neutropenic complications. Both conditional risk factors (e.g., the depth of the first-cycle absolute neutrophil count nadir) and unconditional risk factors (e.g., patient age, treatment regimen, and pretreatment blood cell counts) are predictors of neutropenic complications in early-stage breast cancer. Colony-stimulating factor targeted toward high-risk patients starting in the first cycle of chemotherapy may make it possible for full doses of chemotherapy to be administered, thereby maximizing patient benefit. Recent studies of dose-dense chemotherapy regimens with CSF support in early-stage breast cancer have shown improvements in disease-free and overall survival, with less hematologic toxicity than with conventional therapy. These findings could lead to changes in how early-stage breast cancer is managed.

Age Factors↗

PubMed2006

Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.

Diabetic Neuropathies↗

PubMed2003

Should increasing the dose or adding an AT1 receptor blocker follow a relatively low dose of ACE inhibitor initiated in acute myocardial infarction?

OBJECTIVE: Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI. METHODS: Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks. RESULTS: Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy. CONCLUSIONS: After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1986

Organ specific acute toxicity of the carcinogen trans-4-acetylaminostilbene is not correlated with macromolecular binding.

trans-4-Acetylaminostilbene (trans-AAS) is acutely toxic in rats and lesions are produced specifically in the glandular stomach. Toxicity is slightly increased by pretreating the animals with phenobarbital (PB) and is completely prevented by pretreatment with methylcholanthrene (MC). The prostaglandin inhibitors, indomethacin and acetyl salicylic acid, do not reduce toxicity. The high efficiency of MC suggested that toxicity is caused by reactive metabolites. trans-[3H]-AAS was administered orally to untreated and to PB- or MC-pretreated female Wistar rats and target doses in different tissues were measured by means of covalent binding to proteins, RNA and DNA. Macromolecular binding in the target tissue of poisoned animals was significantly lower than in liver and kidney and comparable to other non-target tissues. Pretreatment with MC lowered macromolecular binding in all extrahepatic tissues but not in liver. These findings are not in line with tissue specific metabolic activation. The only unique property of the target tissue, glandular stomach, that we observed was a particular affinity for the systemically available parent compound. In the early phase of poisoning, tissue concentrations were exceedingly high and the stomach function was impaired.

Animals↗

PubMed1998

Heritable and cancer risks of exposures to anticancer drugs: inter-species comparisons of covalent deoxyribonucleic acid-binding agents.

In the past years, several methodologies were developed for potency ranking of genotoxic carcinogens and germ cell mutagens. In this paper, we analyzed six sub-classes of covalent deoxyribonucleic acid (DNA) binding antineoplastic drugs comprising a total of 37 chemicals and, in addition, four alkyl-epoxides, using four approaches for the ranking of genotoxic agents on a potency scale: the EPA/IARC genetic activity profile (GAP) database, the ICPEMC agent score system, and the analysis of qualitative and quantitative structure-activity and activity-activity relationships (SARs, AARs) between types of DNA modifications and genotoxic endpoints. Considerations of SARs and AARs focused entirely on in vivo data for mutagenicity in male germ cells (mouse, Drosophila), carcinogenicity (TD50s) and acute toxicity (LD50s) in rodents, whereas the former two approaches combined the entire database on in vivo and in vitro mutagenicity tests. The analysis shows that the understanding and prediction of rank positions of individual genotoxic agents requires information on their mechanism of action. Based on SARs and AARs, the covalent DNA binding antineoplastic drugs can be divided into three categories. Category 1 comprises mono-functional alkylating agents that primarily react with N7 and N3 moieties of purines in DNA. Efficient DNA repair is the major protective mechanism for their low and often not measurable genotoxic effects in repair-competent germ cells, and the need of high exposure doses for tumor induction in rodents. Due to cell type related differences in the efficiency of DNA repair, a strong target cell specificity in various species regarding the potency of these agents for adverse effects is found. Three of the four evaluation systems rank category 1 agents lower than those of the other two categories. Category 2 type mutagens produce O-alkyl adducts in DNA in addition to N-alkyl adducts. In general, certain O-alkyl DNA adducts appear to be slowly repaired, or even not at all, which make this kind of agents potent carcinogens and germ cell mutagens. Especially the inefficient repair of O-alkyl-pyrimidines causes the high mutational response of cells to these agents. Agents of this category give high potency scores in all four expert systems. The major determinant for the high rank positions on any scale of genotoxic of category 3 agents is their ability to induce primarily structural chromosomal changes. These agents are able to cross-link DNA. Their high intrinsic genotoxic potency appears to be related to the number of DNA cross-links per target dose unit they can induce. A confounding factor among category 3 agents is that often the genotoxic endpoints occur close to or at toxic levels, and that the width of the mutagenic dose range, i.e., the dose area between the lowest observed effect level and the LD50, is smaller (usually no more than 1 logarithmic unit) than for chemicals of the other two categories. For all three categories of genotoxic agents, strong correlations are observed between their carcinogenic potency, acute toxicity and germ cell specificity.

Animals↗

PubMed2002

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin.

OBJECTIVE: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. BACKGROUND: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. DESIGN/METHOD: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio. RESULTS: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero. CONCLUSIONS: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.

Adolescent↗

PubMed1996

Trigeminal neuralgia radiosurgery: the University of Pittsburgh experience.

The results of Gamma Knife stereotactic radiosurgery in the management of 51 patients who had typical trigeminal neuralgia were evaluated at the University of Pittsburgh. In all cases, a 4-mm isocenter was targeted at the proximal nerve at the root entry zone. The target dose varied from 60 to 90 Gy. Forty-four patients (86%) had undergone prior surgery. The mean follow-up after radiosurgery was 9.6 months (range, 2-29 months). The initial response rate was 86%. At the last follow-up, 19 patients (37%) had excellent control (pain free), 21 (41%) had good control (50-90% relief), and 11 (21%) had failed treatment. No patient developed further sensory loss or deafferentation pain. A maximum radiosurgery dose > or = 70 Gy was associated with a significantly greater chance for complete pain relief. Using magnetic resonance imaging stereotactic targeting, the proximal trigeminal nerve is an appropriate anatomic target for radiosurgery. Gamma Knife radiosurgery is a useful additional surgical approach in the management of medically or surgically refractory trigeminal neuralgia.

Adult↗

PubMed2004

High-versus low-dose ACE inhibitor therapy in chronic heart failure.

OBJECTIVE: To discuss the controversy associated with the optimal dosing of angiotensin-converting enzyme (ACE) inhibitors in the management of patients with systolic heart failure; specifically, to review data related to the use of high-dose ACE inhibitors related to both neurohormonal and clinical outcomes associated with doses similar to, lower than, and higher than those used in the large, randomized clinical trials. DATA SOURCES: Primary, review, and meta-analysis articles were identified by MEDLINE search (1987-September 2002) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this discussion. All available comparative dose trials, both prospective and retrospective, were evaluated for clinical and neurohormonal outcomes. DATA SYNTHESIS: The majority of data comparing the effect of high- with low-dose ACE inhibitors on neurohormonal outcomes demonstrate dose-related reduction in various neurohormonal measurements including plasma ACE, aldosterone, atrial natriuretic peptide, B-type natriuretic peptide, and interleukin-6 levels. Clinical endpoints including New York Heart Association class and heart failure-related hospitalizations were reduced by higher doses, but a dose-related survival benefit has not been demonstrated. Differences in duration of therapy and study design may account for variability in neurohormonal and morbidity results among various studies. CONCLUSIONS: Despite documented underutilization in clinical practice of doses of ACE inhibitors demonstrated in large controlled trials to improve morbidity and mortality, clinicians should attempt to reach these target doses if possible in patients with heart failure. Higher doses may improve surrogate markers for heart failure without impacting survival.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Therapeutic effect of three-dimensional conformal radiotherapy on locally advanced pancreatic carcinoma.

OBJECTIVE: To evaluate the effects of the two conformal radiotherapy modalities in the treatment of locally advanced pancreatic carcinoma. METHODS: From October, 1998 to June, 2001, 67 patients with locally advanced pancreatic carcinoma received conformal radiotherapy (CRT). Vacuum cushions were applied to immobilize the patients before contrast CT scans, the treatment plans were simulated by three-dimensional treatment planning system. The patients were randomized into group A to receive a total dose of 45-54 Gy given in 8-12 fractions completed in 18-27 d and group B with a total dose of 45-54 Gy in 15-18 fractions within 20-25 d. RESULTS: The partial and complete pain relief rates of the two groups were 95.9% and 81.6%, respectively, one month after the completion of the radiotherapy, with a median survival of 12.5 months. The response rates of the patients and the 2-year overall survival rates in group A were 81.8% and 51.6%, respectively, and were 35.3% and 12.1% in group B. The low-dose fractionated CRT was superior than accelerated CRT. CONCLUSION: For patients with unresectable pancreatic cancer receiving low-dose fractionated CRT, a high dose targeted at the tumor can be given in a fraction and the normal surrounding tissues are exposed to low-dose radiation, to achieve good therapeutic effect with minimized adverse effects on normal tissues in relation to the exposure.

Adult↗

PubMed2004

CNI-sparing regimens within the liver transplant setting: experiences of a single center.

One- and 5-year survival rates after liver transplantation have improved with the development of potent immunosuppressive drugs. Thus, attempts have shifted to reduce long-term complications of CNI and prednisone therapy. Minimization of CNI and concomitant introduction of MMF has resulted in a significant improvement of renal function, blood pressure and triglyceride values in our transplant patients. In recipients who develop recurrent or de novo malignancies, SRL therapy might be recommended. In addition, the flexibility to individualize immunosuppression should be favored in selected patients. However, large prospective randomized trials are required in order to determine if SRL/low dose CNI or SRL monotherapy are reasonable options for prolonging patient survival. Moreover, important questions such as the appropriate SRL target dose for prevention of tumor growth need to be answered. Numerous studies investigating distinct immunosuppressive combination therapies and withdrawal or minimization of CNI are available in the literature; however it is not yet clear which treatment regimens will prove to be the most efficacious and least toxic.

Adult↗

PubMed1984

[Whole-skin electrotherapy: a therapeutic concept for mycosis fungoides and Sézary syndrome. I. Irradiation technic and dosimetry].

A simple, but efficient radiotherapeutic method is presented for the irradiation of the whole body surface. Dosimetric measurement shows that the largest part of the skin receives between 80 and 100% of the dose. Only the concave surfaces receive a lower dose. They are saturated by boost irradiation. The total body exposure due to Bremsstrahlung is less than 1% of the target dose.

Electrons↗

PubMed2006

Pharmacokinetic study of memantine in healthy and renally impaired subjects.

OBJECTIVE: Our objective was to evaluate the pharmacokinetics of the Alzheimer's disease treatment memantine in subjects with normal and impaired renal function. METHODS: This was a single-center, single-dose, open-label study. Thirty-two subjects aged 18 to 80 years were assigned to 1 of 4 groups (8 subjects each) based on baseline creatinine clearance: normal renal function (>80 mL/min), mild renal impairment (50-80 mL/min), moderate renal impairment (30-49 mL/min), and severe renal impairment (5-29 mL/min). A single 20-mg memantine dose was administered under fasting conditions. Assessments included pharmacokinetic and safety measures. RESULTS: Thirty-one subjects completed the study. There were no relevant differences in maximum memantine plasma concentration between subjects with normal and impaired renal function of any severity. The mean area under the plasma concentration versus time curve extrapolated to infinity was similar between subjects with normal and mildly impaired renal function but increased by 60% (95% confidence interval [CI], 24%-97%) and 115% (95% CI, 77%-152%) in subjects with moderate and severe renal impairment, respectively. Simulations predicted steady-state maximum concentration values of 82 ng/mL (95% CI, 70-95 ng/mL), 85 ng/mL (95% CI, 70-101 ng/mL), and 128 ng/mL (95% CI, 109-147 ng/mL) in healthy subjects, those with mild renal impairment, and those with moderate renal impairment, respectively, for the recommended dosing regimen of 10 mg twice daily; for subjects with severe renal impairment, a steady-state maximum concentration value of 84 ng/mL (95% CI, 68-101 ng/mL) was predicted for a dosing regimen of 5 mg twice daily. CONCLUSION: On the basis of the predicted steady-state plasma concentrations with the use of the current dosing regimen of 10 mg twice daily, no dosage adjustments are needed for patients with mild or moderate renal impairment. A target dose of 5 mg twice daily is recommended in patients with severe renal impairment.

Adolescent↗