Cmin Values Research Articles

Modeling runoff and sediment yields from combined in-field crop practices using the Soil and Water Assessment Tool

Cropland best management practice recommendations often combine improvements to both tillage and fertilizer application practices to reduce sediment losses with surface runoff. This study evaluated the impact of conventional-till and no-till management practices with surface or deep-banded fertilizer application in sorghum-soybean rotation on runoff and sediment-yield predictions using the Soil and Water Assessment Tool (SWAT) model. The model was calibrated using USDA Natural Resources Conservation Service runoff curve number for antecedent moisture condition II (CNII), saturated hydraulic conductivity, and available water capacity parameters for runoff and USLE cropping factor (Cmin) for sediment-yield predictions for three field plots (0.39 to 1.46 ha [0.96 to 3.6 ac]) with different combinations of practices and validated for three field plots (0.40 to 0.56 ha [1.0 to 1.4 ac]) over a period of 2000 to 2004. Surface runoff calibration required CNII values greater than the recommended baseline values. No-till treatments required slightly greater curve number values than the till treatment, and this difference was similar to that associated with increasing the soil hydrologic group by one classification. Generally the model underpredicted the sediment yield for all management practices. Baseline Cmin values were adequate for treatments with soil disturbance, either by tillage or fertilizer deep-banding, but best-fit Cmin values for field conditions without soil disturbance (no-till with surface-broadcast fertilizer) were 2.5 to 3 times greater than baseline values. These results indicate current model limitations in modeling undisturbed (no-till) field management conditions, and caution that models calibrated for fields or watersheds predominated by tilled soil conditions may not function equally well in testing management scenarios without tillage.

Correlations between Kinetic Parameters of Phosphate Uptake and Internal Phosphorus Concentrations in Maize Plants: Making it Possible to Estimate the Status of Phosphate Uptake according to Shoot Phosphorus Concentrations

The relationship between internal phosphorus (P) concentration [P] and kinetics of phosphate (Pi) uptake was investigated in maize seedlings grown hydroponically at different Pi concentrations (0.1–1,000 µM) and in the phase of Pi deprivation (0–10 d). The results indicated when the internal [P] was higher than 85 µmol g−1 dw, apparent Km, Cmin, and Vmax were significantly (P<0.01) related to [P]s in shoots and roots; when the internal [P] was lower than 85 µmol g−1 dw, Km and Cmin were small and only Vmax was significantly related (P<0.01) to internal [P]s. Three equations were deduced from the linear regressions of the kinetic parameters and [P]s in shoots. Using these equations, the values of apparent Km, Cmin, and Vmax of Pi uptake of seedlings grown in different circumstances were calculated according to [P]s in shoots. In all the circumstances involved, for Km and Cmin, there was a parallel relationship between the values estimated by [P]s in shoots and by the Pi‐depletion technique; for Vmax, the values estimated by [P]s in shoots were consistent with those obtained from Pi‐depletion experiments except the period of supplying Pi to the Pi‐starved seedlings over several days. These results indicated it is possible to estimate the Pi‐uptake status according to shoot P concentrations in maize plants under experimental conditions, which might be helpful to estimate in‐season status of Pi uptake of maize plants in the field.

Relative Phosphorus Utilization Efficiency, Growth Response, and Phosphorus Uptake Kinetics of Brassica Cultivars under a Phosphorus Stress Environment

Plants grown in highly weathered or highly alkaline calcareous soils often experience phosphorus (P) stress but never a P‐free environment. Thus, applications of mineral P fertilizers are often required to achieve maximum yield, but recovery of applied P fertilizers is notoriously low. Phosphorus deprivation elicits a complex array of morphological, physiological, and biochemical adaptations among plant species and genotypes to enhance P acquisition and utilization efficiency. Ten Brassica cultivars were grown hydroponically to investigate their relative efficiency to utilize deficiently (20‐µM) and adequately (200‐µM) supplied P, using Johnson's modified solution. Cultivars differed significantly (P<0.001) in biomass accumulation. Orthophosphate concentration and uptake in shoot and root, absolute and relative growth rate, and P‐utilization efficiency (PUE) were also significantly different among various Brassica cultivars. Root‐shoot ratio and specific absorption rate were substantially increased in plants subjected to low P supply. Shoot and root dry‐matter yield as well as total biomass production correlated significantly (P<0.01) with their total P uptake and PUE. Cultivars, which were efficient in P utilization, were also efficient accumulators of biomass under adequate as well as deficient levels of P supply. As part of the study, kinetic parameters of P uptake were evaluated for six contrasting Brassica cultivars in PUE, grown in nutrient solution. The kinetic parameters related to P influx were maximal transport rate (Vmax), the Michaelis–Menten constant (Km), and the external concentration when net uptake is zero (Cmin). Lower Km and Cmin values were indicative of P‐uptake ability of the cultivars, evidencing their adaptability to P‐stress conditions. In another experiment, six cultivars were exposed to no P nutrition for 27 days after initial feeding on optimum nutrition for 14 days. All the cultivars retranslocated P from aboveground parts to their roots during growth in P‐free conditions, the magnitude of which was variable in different cultivars. Phosphorus concentration at 41 days after transplanting was higher in developing leaves than developed leaves. Translocation of absorbed P from metabolically inactive sites to active sites in plants growing under P‐stress conditions may have helped the tolerant cultivars to establish a better rooting system, which provided basis for tolerance against P‐deficiency stress and increased PUE.

Therapeutic Drug Monitoring of Imatinib and Impact on Clinical Decision Making.

OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making.METHODS: IM trough blood samples were collected at a time before that day's IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method.RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability.CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice.Patient IDAge, SexCML StageIM Daily Dose1st Cmin (ng/mL)Reason for Dose ChangeNew Dosing RegimenNew Cmin (ng/mL)154, fCP200 mg bid, Jan 033048, Sep 05transfusion-dependent, anemia, Sep 05300 mg, Oct 052130, Jan 0629, fCP300 mg, Jan 05not doneqRT-PCR 0.016, Jan 06400 mg, Jan 062341, Jul 06313, fCP300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 051966, Feb 06nausea, fatigue, arthralgias, myalgia, ongoing400 mg, Mar 061222, May 06467, fCP400 mg, Feb 05not donemyelosuppression, Mar 05200 mg, Mar 051928, May 06553, fCP400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04not doneinflammatory pulmonary reaction with shortness of breath; dose held, Mar 05400 mg, Oct 052378, May 06673, mCP350 mg, on phenytoin, Apr 9935, Jun 99stopped phenytoin, Jul 99500 mg, Jul 99not done; qRT-PCR negative, Jul 06CP, chronic phase1

Pharmacokinetics-pharmacodynamics of micafungin in Japanese patients with deep-seated mycosis

The objective of this study was to describe the pharmacokinetic profile and investigate the effective concentration of micafungin in Japanese male patients with deep-seated mycosis. 66 patients were treated with i.v. micafungin 12.5-150 mg intravenously for up to 56 days. At this dose range, micafungin showed linear pharmacokinetics, and the mean values of Cmax and Cmin amounted to 3.16-12.9 microg/mL and 0.70-3.68 microg/mL, respectively. The mean value for the elimination half-life was 13.5 h (95 samples from 65 patients), and it remained almost constant over the dose range. In addition, the elimination half-life was not influenced by age, gender or weight, and was similar to that found in healthy subjects. The active metabolites M1 and M2 were detectable, but their exposure was lower than that of the unchanged drug. The pharmacokinetic-pharmacodynamics ob micafungin were then investigated. The overall clinical response rate against aspergillosis and candidiasis showed good results at a dose of 50 mg and over. The Cmax and Cmin at the latter dose amounted to 5.16 and 1.41 microg/mL, respectively. In conclusion, micafungin showed linear pharmacokinetics at doses ranging from 12.5 to 150 mg, and the effective concentration was considered to be over 5 microg/mL as maximum level in Japanese patients with deep-seated mycosis such as candidiasis and aspergillosis.

Lack of Interaction Between Atazanavir and Proton Pump Inhibitors in HIV-Infected Patients Treated With Ritonavir-Boosted Atazanavir

To the Editor: Conflicting results have been recently published concerning drug interaction between atazanavir (ATV) and antacid treatments, especially proton pump inhibitors (PPIs). In the August 1, 2005 issue of this journal, Khanlou and Farthing1 summarized the results they collected in 10 HIV clinics in Los Angeles, saying that the use of ATV, even boosted with ritonavir (RTV), with PPIs should be avoided. These data require some comments. In this study, the prospective method of plasma collection is not clearly defined. Were the patients interviewed by a physician on the treatment they were really taking? Did the nurse who drew the blood samples ask the patients when they had taken their last dose of ATV and antacid treatment? The median ATV minimum concentrations (Cmins) reported are not in keeping with values observed in recent published studies and in our experience on HIV-infected patients treated with boosted ATV (Table 1).TABLE 1: Median ATV Cmin in Patients Treated With Boosted ATV (300/100 mg/d)Because of its chemical structure, ATV absorption is highly dependent on an appropriate gastric pH. The potential interaction between ATV and PPIs or histamine-2 receptor blockers (H2RBs) is expected to reduce ATV exposure. In the presence of an H2RB, however, the median ATV Cmin reported in this study was 2-fold higher than values observed in the previously reported series (performed in patients without antacid treatment). Such a high ATV Cmin was found in only 1 study on healthy volunteers.2 In presence of PPIs, the median ATV Cmin was found to be strictly comparable to those observed in the previous studies, where a significant reduction should be expected. These results could be explained by too short a time between blood sample collection and drug intake. Assessing the time between ATV intake and blood collection precisely is fundamental in such a study. Only ATV plasma concentrations measured 24 ± 4 hours (Cmin) after the last intake should be taken into account in patients who have received a stable ATV regimen for at least 1 week before blood sampling. Treatments received by the patients included in this study should be detailed. The proportion of patients receiving ATV boosted with RTV may indeed highly influence the Cmin values observed. The results collected in such patients should therefore be distinguished from those collected in patients receiving ATV without RTV. In our prospective cohort of 184 patients, median Cmins measured at 24 ± 4 hours were 499 [26-2205] ng/mL and 99 [12-1159] ng/mL among the 141 patients treated with 300 mg of ATV plus 100 mg of RTV and the 43 patients receiving 400 mg of ATV alone, respectively (P < 0.0001). The combination of ATV with another protease inhibitor or nonnucleoside reverse transcriptase inhibitor may lead to significant drug interactions and should also be noted. During PPI treatment, the time during which the intragastric pH is above 4.0 increases with the acid-suppressive dose, and pH can vary widely during the day in a given individual. Doses of PPIs may affect ATV absorption differently and have to be precisely described. The time interval between ATV and antacid drug administration may also play a role. This is a possible confusion bias if patients did not state the time of their last drug intake accurately. In our cohort, we prospectively compared ATV Cmin in HIV-infected patients receiving ATZ plus RTV, with or without a PPI, to assess this specific drug interaction in clinical practice. Among the first 92 patients enrolled, 13 stated that they were taking a PPI. Among these 13 patients, 10 were using omeprazole (20 mg/d, except for 1 patient who was taking 40 mg/d) and 3 were using rabeprazole (30 mg/d). Median ATV trough concentrations were 551 ng/mL (range: 203-1976 ng/mL) in the patients receiving PPIs and 469 ng/mL (range: 65-1944 ng/mL) in the group without PPIs. Results showed that PPI treatment did not affect ATV Cmin values in our patients.3 A recent case report with pharmacokinetic study showed no interaction between boosted ATV and lansoprazole. Another study showed no clinical or immunovirologic failures in 14 patients treated with ATV and PPIs after a 6-month follow-up.4,5 Our findings are in keeping with these results. Our conclusion is therefore completely different from that of Khanlou and Farthing1 because we observed that PPIs seem to be compatible with boosted ATZ therapy in clinical practice. It is nonetheless recommended to monitor ATV drug concentrations in case of concomitant antacid treatment. Jean-Baptiste Guiard-Schmid, MD* Jean-Marie Poirier, MD† Philippe Bonnard, MD* Jean-Luc Meynard, MD† *Service des Maladies Infectieuses et Tropicales Hôpital Tenon †Service de Pharmacologie Faculté de Médecine St. Antoine and ‡Service des Maladies Infectieuses et Tropicales Hôpital St. Antoine Université Pierre et Marie Curie (Paris VI) Paris, France

Pharmacokinetic Parameters of Nevirapine and Efavirenz in Relation to Antiretroviral Efficacy

Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).

Proton Pump Inhibitor Therapy in Atazanavir-Treated Patients

Proton Pump Inhibitor Therapy in Atazanavir-Treated Patients

Parâmetros cinéticos e morfológicos da absorção de nutrientes em cultivares de milho com variabilidade genética contrastante

Genótipos de milho com variabilidade genética contrastante apresentam potenciais produtivos diferentes. Isso pode ser causado, pelo menos em parte, por diferenças morfológicas no sistema radicular e nos parâmetros cinéticos de absorção de nutrientes. Este trabalho objetivou quantificar esses parâmetros em três cultivares de milho. Foram comparados um híbrido simples (HS), um híbrido duplo (HD) e uma variedade de polinização aberta (VPA). Determinaram-se os parâmetros de absorção (influxo máximo, Imax, constante de Michalies-Menten, Km, e concentração na solução onde a absorção cessa, Cmin) para N, P, K, Ca e Mg, além de atributos morfológicos radiculares, em experimentos efetuados em câmara de crescimento, com solução nutritiva. A morfologia das raízes variou pouco entre os genótipos, provavelmente por causa do cultivo das plantas em meio líquido. As diferenças entre genótipos quanto aos parâmetros cinéticos de absorção dependeram do nutriente. O Imax diferiu entre os cultivares para P; o Km, para N e P, e o Cmin, para N e K. A VPA, por apresentar maior variabilidade genética, deveria apresentar menores valores para Km e Cmin do que os híbridos. Contudo, isso só aconteceu para P em relação ao Km. O HS, por apresentar maior potencial produtivo, deveria expressar os maiores valores para Imax, mas isso não ocorreu com nenhum dos macronutrientes avaliados. Portanto, a absorção de nutrientes não parece ser um fator determinante nas diferenças de rendimento de grãos entre genótipos de milho com bases genéticas contrastantes.

Cinética de absorção e eficiência nutricional de K+, Ca2+ e Mg2+ em plantas jovens de quatro clones de eucalipto

Modelos mecanísticos baseados em princípios de transporte de solutos pode ser de grande utilidade para prever os impactos do cultivo de florestas plantadas, por exemplo, com eucalipto sobre o capital e fluxo de nutrientes no solo. Dentre as variáveis de entrada demandadas por tais modelos, tem-se os valores das constantes Vmax, Km e Cmin da cinética de absorção iônica. Assim, os objetivos do presente trabalho foram determinar os valores de Vmax, Km e Cmin para K, Ca e Mg, bem como avaliar as respectivas eficiências nutricionais de clones de eucalipto. O estudo consistiu de três ensaios em solução nutritiva (um para cada cátion), sendo utilizadas mudas propagadas vegetativamente de um híbrido de E. grandis x E. urophylla (clone 1213) e de três híbridos de E. grandis (clones 7074, 57 e 129). Com base nos teores de cada um desses nutrientes nas soluções de depleção, em cada tempo de amostragem, no volume inicial e final de solução nos vasos e no peso de matéria fresca de raízes, foram obtidos os valores das constantes cinéticas. Para K, o clone 7074 apresentou o menor valor de Vmax em relação aos demais clones, os quais não diferiram entre si, e em relação ao Km e Cmin, os clones não diferiram estatisticamente. Para Ca, os clones estudados diferiram quanto ao valor de Vmax e Km, não diferindo, entretanto, para o Cmin. Os menores valores de Km para Mg foram verificados para os clones 57 e 7074, ou seja, as proteínas transportadoras de Mg na membrana plasmática das células radiculares apresentaram maior afinidade para esse nutriente. Contudo, os valores de Vmax e Cmin não diferiram entre os clones estudados. Diferenças na eficiência nutricional dos clones estudados quanto a K e a Ca foram devidas às diferenças na eficiência de absorção, e para Mg às diferenças na eficiência de absorção e de utilização.

Are Adverse Events of Nevirapine and Efavirenz Related to Plasma Concentrations?

The relationships between adverse events (AEs) and plasma concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part of the large, international, randomized 2NN study. Treatment-naive, HIV-1-infected patients received NVP (once or twice daily), EFV or their combination, each in combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian estimates of the area under the plasma concentration-time curve over 24 h (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as measures for drug exposure of NVP and EFV, were generated using a previously developed population pharmacokinetic model. Pharmacokinetic parameters were compared for patients with and without central nervous system (CNS) and psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic parameter could be identified above which the incidence of AEs was clearly increased. AEs were also related to demographic parameters and baseline characteristics. In total, from 1077 patients, NVP (3024 samples) and EFV (1694 samples) plasma concentrations and AE data (825 observations) were available. For all patients Cmin, Cmax and AUC24h were determined. When corrected for known covariates of gender, CD4 cell count at baseline, region, hepatitis coinfection and possible interactions between these factors, no significant associations between AEs and any tested exposure parameter of NVP was observed. Also, no target Cmin value, above which patients were at increased risk for AEs, could be established. On the other hand, geographical region, hepatitis coinfection, CD4 cell count and gender were found to be significantly related with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash during the treatment with NVP. The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk for elevated liver enzymes. No other correlations between AEs and EFV pharmacokinetics or patient characteristics could be identified. Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN trial when corrected for known covariates. The value of periodical drug monitoring of NVP as a way to prevent toxicity is therefore limited. Treating physicians should instead focus on factors that are more predictive of AEs (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in elevated liver enzyme values during the first 6 weeks of treatment. Regular measurement of EFV levels and liver enzymes at the start of therapy may therefore be advised.

Effect of temperature and moisture on rates of carbon mineralization in a Mediterranean oak forest soil under controlled and field conditions

SummaryWe examined the relationship between carbon mineralization (Cmin), moisture and temperature in a Mediterranean forest soil under controlled and field conditions. We studied the following.1 The temperature sensitivity at three soil depths: soil samples were incubated at 4, 10, 20 and 30°C at optimal water content of 60% of water holding capacity (WHC). Values ofCminof the top layer were more than 12 times faster than those measured in deeper layers. We found a temperature sensitivity factor (Q10) of 3.3, 2.7 and 2.2 for the 0–5 cm, 5–10 cm and 10–20 cm layers, respectively.2 The relationship betweenCmin, moisture and temperature (top layer). The sensitivity ofCminto fluctuating moisture depended on temperature. However, theQ10was not significantly affected by soil moisture. We fitted a multiple polynomial model that predictedCminas a multiplicative function of temperature and moisture (R2 &gt; 0.99).3 The response ofCminof soil to rewetting after 1 and 24 hours. In all cases, the response was rapid. The soil incubated at 60% WHC or less responded positively to a sudden increase in water content, with the largest increase in the 20% WHC treatment. The model predictedCminin the field well when rewetting effects were taken into account (R2 &gt; 0.81).These results indicate that sudden changes in soil moisture can lead to increased carbon mineralization during the dry summer. It is necessary to include such responses in models as they may represent a substantial loss of carbon in the overall carbon balance of Mediterranean ecosystems.

Voriconazole, a novel wide‐spectrum triazole: oral pharmacokinetics and safety

Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg-1 twice daily, 4 mg kg-1 once daily, 2 mg kg-1 three times daily, or 3 mg kg-1 twice daily. Eleven subjects received 1.5 mg kg-1 three times daily, and 21 subjects were administered placebo. Voriconazole exhibited nonlinear (dose- and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCtau. The absorption of voriconazole was rapid (mean tmax= 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after tmax was generally biphasic. By day 12, the Cmax, AUCtau, tmax, and t1/2 values for the 3 mg kg-1 twice-daily group were 2356 ng ml-1, 11 170 ng.h ml-1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for Cmax and AUCtau, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg-1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCtau values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens (Cmin > 0.8 micro g ml-1). Voriconazole was well tolerated: most treatment-related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg-1 twice daily.

Pharmacokinetics, food intake requirements and tolerability of once‐daily combinations of nelfinavir and low‐dose ritonavir in healthy volunteers

This study was performed to evaluate the steady-state pharmacokinetics, food intake requirements and short-term tolerability of once-daily combinations of nelfinavir and low-dose ritonavir. Twenty-seven healthy volunteers were randomized over three groups to receive a once-daily regimen of nelfinavir/ritonavir 2,000/200 mg (group 1), 2,000/400 mg (group 2) or 2,500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively. Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC(24h) values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24-h Cmin concentrations of nelfinavir were 0.76 mg l(-1), 0.43 mg l(-1) and 0.47 mg l(-1), respectively. Co-administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC(24h) and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1,250 mg BID without ritonavir). In the 2,000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l-1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC(24h) and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67-0.86, participants from all groups combined). Short-term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%). Administration of nelfinavir in a once-daily regimen appears feasible. A nelfinavir/ritonavir 2,000/200 mg combination appears appropriate for further evaluation. Once-daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.

Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients

To evaluate the pharmacokinetics, efficacy and tolerability of a low-dose boosted indinavir (IDV)/ritonavir (RTV) regimen [100 mg RTV/400 mg IDV twice daily (bid)] in patients previously receiving a standard IDV regimen [800 mg three times a day (tid)]. In a prospective, open-label, cross-over trial, patients with plasma HIV RNA < 200 copies/ml receiving an IDV-containing regimen (800 mg tid) were switched to an RTV/IDV (100/400 mg bid)-containing regimen. Minimal and maximal IDV plasma concentrations ( Cmin and Cmax ) were determined before the switch (day 0), at week 2 and week 4 after the switch. The CD4 cell count and plasma HIV RNA were determined at day 0, week 2 and week 4, then every 8 weeks. The primary end-point was the percentage of patients with plasma HIV RNA below 200 copies ml at week 48. Twenty patients were enrolled. At baseline, on IDV 800 mg tid, median IDV Cmin was 194 ng/ml and median IDV Cmax was 8449 ng/ml. On RTV/IDV (100/400 mg), median IDV Cmin increased to 536 ng/ml at week 2 and 475 ng/ml at week 4, while Cmax decreased to 2983 ng/ml at week 2 and 2997 ng/ml at week 4 ( P < 0.001). The median area under the IDV plasma concentration-time curve measured in seven patients was 25 126 ng.h/ml, and the IDV half-life (t1/2 ) was 4.4 h. All patients had plasma HIV RNA remaining < 200 copies/ml at week 48. Tolerability of RTV/IDV was excellent. RTV/IDV (100/400 mg bid) yields significantly higher IDV plasma Cmin and lower IDV Cmax values relative to the standard IDV regimen, thereby improving both tolerability and efficacy.

Phosphorus and Potassium Uptake Kinetics in Red Maple Seedlings

Abstract Acquisition of nutrients by tree roots generally is viewed as a complex process. Models that make use of Michaelis-Menten kinetics concepts provide a means to mechanistically simulate nutrient uptake. The objectives of this study were to provide: (1) estimates of the Michaelis-Menten parameters Imax, Km, and Cmin for P and K uptake by red maple (Acer rubrum L.) seedlings, and (2) to test the efficacy of these values in the modeling context by using the Barber-Cushman nutrient uptake model as a test vehicle. A nutrient depletion approach that used intact seedlings and transient conditions was used to define the kinetics values. These estimates were combined with literature values to provide a full parameter set for the model. Uptake of P proceeded rapidly and yielded an average Imax of 5.5E-6 μmol cm-2 s-1. Mean Km and Cmin values for P were 15.0 and 0.001 μmol mL-1, respectively. Potassium uptake was slower with a mean Imax of 3.8E-6 μmol cm-2 s-1, and the Km and Cmin values were 10.5 and 0.003 μmol mL-1, respectively. Simulated P uptake compared poorly with observed uptake (0.8 vs. 830 μmols). However, additional model runs indicated that the lack of agreement was more the result of a low estimate of soil solution P concentration than a problem with the P kinetics values. Simulated K uptake was in much better agreement with the observed value (891 vs. 1890 μmols). The Cmin values for P and K reflect an ability to continue root uptake at extremely low solution concentrations. This may contribute to the “supergeneralist” status accorded red maple. This study indicates these Imax, Km, and Cmin values can be used in the Barber-Cushman model to simulate P and K uptake by red maple. However, use of these Imax, Km, and Cmin values needs to be tempered with the understanding that several interacting factors influence uptake. This caveat is important when generic literature values provide some or all of the numbers used to initialize the model. FOR. SCI. 47(3):397–402.

Pharmacokinetic Basis for the Efficient and Safe Use of Low-Dose Mycophenolate Mofetil in Combination with Tacrolimus in Kidney Transplantation

Mycophenolate mofetil (MMF) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A (CsA) or tacrolimus (Tc). An increase in plasma mycophenolic acid (MPA) has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship for MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc. Adult kidney transplant recipients (n = 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained within the first 2 weeks after transplantation, 3 months after grafting, and at every adverse clinical event [side effect or acute rejection (AR)]. All patients received Tc, MMF (500 mg twice a day), and steroids. Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total of 78 MPA-PK profiles were obtained. The following PK parameters were increased in the side-effects group compared with the non-side effects group: mean MPA c(min), 2.63 +/- 1.58 vs 1.75 +/- 0.82 mg/L (P = 0.016); mean c(30), 10.47 +/- 6.27 vs 7.66 +/- 8.95 mg/L (P = 0.009); mean c(60), 9.67 +/- 5.42 vs 5.83 +/- 2.6 mg/L (P = 0.0002); mean area under the MPA time-concentration curve from 0 to 12 h [MPA-AUC((0-12))], 48.38 +/- 18.5 vs 36.04 +/- 10.82 mg. h/L (P = 0.0006); mean dose-normalized MPA-AUC, 0.16 +/- 0.05 vs 0.12 +/- 0.04 (mg. h/L)/(mg/m(2)) (P = 0.0015). For the three AR patients, MPA concentrations obtained at the time of AR revealed MPA c(min) values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC((0-12)) values of 37.7, 24.9, and 104.9 mg. h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7%; specificity, 91.5%) for c(min), 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg. h/L for MPA-AUC((0-12)) (sensitivity, 83.3%; specificity, 59.6%). These results demonstrate the relationship between plasma MPA concentrations and toxicity. High c(min), c(30), and c(60) values as well as AUC((0-12)) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program.

Clinical pharmacokinetics of mizolastine.

Mizolastine is a new histamine H1 receptor antagonist. Mizolastine 10 mg/day is effective in allergic rhinitis and chronic idiopathic urticaria. In young healthy volunteers, absorption of mizolastine is rapid with time (tmax) to peak concentration (Cmax) of about 1 hour. The absolute bioavailability of mizolastine 10mg tablets is about 65%. Distribution is rapid with a mean distribution half-life of 1.5 to 1.9 hours. Mizolastine is >98% bound to serum albumin and the apparent volume of distribution is between I and 1.4 L/kg. Mizolastine is extensively metabolised by hepatic glucuronidation and sulphation, with no major active metabolite, and excreted in faeces. The terminal elimination half-life (t1/2beta) is 7.3 to 17.1 hours. The apparent oral clearance after a repeated oral dose of 10mg is 6.02 L/h, with steady state reached from day 3 and no accumulation between days 1 and 7. Cmax and area under the concentration-time curve (AUC) are linearly related to dose. Mizolastine appears in vivo to be a relatively weak inhibitor of cytochrome P450 2E1, 2C9, 2D6 and 3A4. In vivo, no interactions were observed between mizolastine and lorazepam or ethanol. A significant increase in Cmax and trough plasma concentration (Cmin) of digoxin occurred after coadministration with mizolastine, without change in AUC, tmax or clinical parameters. Significant increases in theophylline Cmin and AUC were observed after coadministration with mizolastine. Mizolastine Cmax and AUC were increased when coadministered with erythromycin, with no change in t1/2beta. Concomitant administration of mizolastine and ketoconazole increased mizolastine AUC values with no change in t1/2beta. In a population analysis of the pharmacokinetics of mizolastine in patients with allergies, parameter values were close to those in healthy volunteers, except for duration of absorption, which was almost doubled in the patients. Bodyweight and creatinine clearance were found to have little influence on oral clearance, and no influence of liver transaminases was found on clearance and distribution. Pharmacokinetic parameters of mizolastine in elderly individuals were similar to those observed in healthy young volunteers. In patients with chronic renal insufficiency, t1/2beta was prolonged by 47% compared with young healthy volunteers. In patients with cirrhosis, tmax was longer, Cmax was lower, distribution half-life was prolonged and AUC was 50% higher than in healthy volunteers. In pharmacodynamic-pharmacokinetic trials, the percentage of wheal and flare inhibition was found to correlate with mizolastine Cmin values. No direct relationship was found between drug concentrations in skin blister fluid and antihistamine activity.

The Effect of Telmisartan on the Steady‐State Pharmacokinetics of Digoxin in Healthy Male Volunteers

A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Dose-Finding Study of Once-Daily Indinavir/Ritonavir Plus Zidovudine and Lamivudine in HIV-Infected Patients

Background: Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels. Methods: Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 μg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half. Results: In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 × 106/L (range, 4-623 × 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 μg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in μg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was ≥0.1 μg/ml. Conversely, IND Cmin was <0.1 μg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily. Conclusion: Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.