Italian consensus statement on paediatric HIV infection.

The objective of this document is to identify and reinforce current recommendations concerning the management of HIV infection in infants and children in the context of good resource availability. All recommendations were graded according to the strength and quality of the evidence and were voted on by the 57 participants attending the first Italian Consensus on Paediatric HIV, held in Siracusa in 2008. Paediatricians and HIV/AIDS care specialists were requested to agree on different statements summarizing key issues in the management of paediatric HIV. The comprehensive approach on preventing mother-to-child transmission (PMTCT) has clearly reduced the number of children acquiring the infection in Italy. Although further reduction of MTCT should be attempted, efforts to personalize intervention to specific cases are now required in order to optimise the treatment and care of HIV-infected children. The prompt initiation of treatment and careful selection of first-line regimen, taking into consideration potency and tolerance, remain central. In addition, opportunistic infection prevention, adherence to treatment, and long-term psychosocial consequences are becoming increasingly relevant in the era of effective antiretroviral combination therapies (ART). The increasing proportion of infected children achieving adulthood highlights the need for multidisciplinary strategies to facilitate transition to adult care and maintain strategies specific to perinatally acquired HIV infection.

Oral valganciclovir treatment in newborns with symptomatic congenital cytomegalovirus infection.

This study was performed to assess oral valganciclovir V-GCV (GCV pro-drug), 15 mg/kg bid for 6 weeks to 13 neonates with symptomatic congenital cytomegalovirus (CMV). We monitored plasma levels of GCV within 30 days of therapy: C(trough), and C(2h) (before and the 2 hours after administration), we performed viral assessment in plasma and urine and tolerability at baseline, and every fortnight. Pharmacokinetics showed GCV stable and effective plasma concentrations: mean C(trough) = 0.51 +/- 0.3 and C(2h) : 3.81 +/- 1.37 microg/ml. No significant variability was seen neither intra-patient nor inter-patients. One newborn discontinued therapy because of thrombocytopenia, another finished with a neutrophils count of 1,000/microl. At the end of therapy 6 out of 12 and 8 out of 12 newborns were negative for CMV in urine and plasma. The 4 newborns positive for CMV DNA showed a 90% reduction of pre-therapy values. Clinically, the 4 patients reporting hepatic disease and the 3 with thrombocytopenia recovered after 6 weeks of therapy. Eight newborns suffered from SNHL; at the 6-month follow-up no patients had worsened, 2 had improved, and no deterioration was reported in 3 newborns with chorioretinitis scarring. The paucity of adverse events, and the effectiveness and stability of drug plasma concentrations are the important findings of our study.

A new sensitive enzyme-linked immunosorbent assay (ELISA) for Alemtuzumab determination: development, validation and application.

Alemtuzumab is a humanized (IgG(1)) rat monoclonal antibody to CD52 antigen and is currently used in the treatment of chronic lymphocytic leukemia (CLL) and other CD52-positive lymphoproliferative disorders. Various techniques have been developed to measure Alemtuzumab levels in human serum/plasma. The authors report on the validation of a very sensitive enzyme-linked immunosorbent assay (ELISA) to measure serum concentrations of the humanized IgG(1) using a rabbit polyclonal antibody specifically produced against the rat sequence of Alemtuzumab after papain digestion. The assay was successfully applied to test the serum samples of patients with B-lymphocyte CLL who received Alemtuzumab subcutaneously. This ELISA assay could be easily used to determine human serum levels of Alemtuzumab pre- and post-treatment to optimize dosing and scheduling and to study the relationship between dose and clinical response.

Endogenous beta-endorphins in hypertension: correlation with 24-hour ambulatory blood pressure.

OBJECTIVES: The aims of this study were to determine whether hypertensive patients showed increased endogenous opioid tone and to find a possible correlation between beta-endorphin levels and 24-h ambulatory blood pressure. We also investigated whether circulating beta-endorphin levels were associated with pain perception at rest. BACKGROUND: Experimental studies suggest an involvement of the endogenous opioid system in cardiovascular control mechanisms. METHODS: We determined baseline beta-endorphin plasma levels by radioimmunoassay in 81 consecutive subjects (48 hypertensive, 33 normotensive) after a 30-min rest and before 24-h ambulatory blood pressure monitoring. In 72 of 81 subjects with a dental formula suitable for the pulpar test (graded increase of test current -0 to 0.03 mA applied to three healthy teeth), pain perception was also investigated. RESULTS: Hypertensive patients showed higher beta-endorphin plasma levels than normotensive subjects (p < 0.002). Circulating endogenous opioid levels correlated with 24-h diastolic blood pressure (p < 0.01), whereas the relation with systolic pressure did not reach statistical significance. When 24-h blood pressure recordings were divided into daytime and nighttime values, and blood pressure loads (percent of measurements > or = 140 mm Hg for systolic blood pressure and > or = 90 mm Hg for diastolic pressure) were calculated, a significant correlation was found between beta-endorphin levels and diastolic pressures and load. Similarly, presampling diastolic blood pressure was significantly correlated with beta-endorphin levels. Of the 72 subjects tested, hypertensive patients showed a lower pain sensitivity than normotensive subjects. A positive correlation was found between pain threshold and circulating beta-endorphin levels (p < 0.05). CONCLUSIONS: Sustained arterial pressure is probably involved in the tonic activation of cardiovascular mechanisms linked to endogenous opioid tone. Circulating plasma endorphins may account, at least in part, for the pain perception pattern relating to blood pressure levels at rest.

All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase.

Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.

New strategies in immunosuppression.

New immunosuppressive strategies that can prevent both acute and chronic rejection are being investigated to achieve graft tolerance and to minimize side effects and toxicity that may lead to graft loss. Drug pharmacokinetics and pharmacodynamics, as well as pharmacogenetics, all play a role in customizing treatment to the individual patient. To improve patient compliance, new drug formulations are on trial, such as the modified- release oral form of tacrolimus MR4 for once daily administration, which seems to be equivalent to bid administration in terms of steady-state exposure. Monoclonal/polyclonal antibodies are increasingly used in the induction phase in protocols where steroids are discontinued early. However, discontinuing steroids carries a high risk of acute rejection or organ failure in some subgroups of patients. The supposed benefit of steroid discontinuation may not be enjoyed by all patients. Minimizing anticalcineurin agents may prove to be similarly or even more advantageous. The use of new drugs and new combinations has greatly improved short-term transplant outcomes. The new goal is, therefore, to improve long-term results and particularly to prevent chronic rejection, thus increasing patient and organ survival.

Assessment of an LC-MS method for plasma quantification of the new immunosuppressant FK778 through comparison with HPLC-UV.

FK778 is a new immunosuppressive agent, derived from the leflunomide-active metabolite A77 1726. It inhibits de novo pyrimidine nucleotide synthesis showing efficacy in the prevention and treatment of rejection in experimental transplant models. The aim of this work was to develop an HPLC-MS method to measure FK778 in plasma for pharmacokinetic studies. The equipment used for mass evaluation was an HLPC coupled to an ion trap analyzer through an electrospray source. After precipitation of plasma proteins with acetonitrile, the supernatant was injected onto an analytical RP-C18 column. Chromatographic separation was performed under isocratic conditions, using a mobile phase consisting of ammonium acetate buffer and acetonitrile (55:45. vol/vol). MS detection was performed in the negative ionization mode by monitoring the molecular ion of FK778 (m/z 307) and IS (m/z 269), using selected ion monitoring for both. However, we observed peaks corresponding to dimers, trimers, and tetramers of FK778 (m/z 637, m/z 945, m/z 1274). The HPLC-MS method was applied to pharmacokinetics in animal models showing comparable results to those obtained by an HPLC-UV assay at 290 nm. Good agreement was observed in the plasma FK778 concentration versus time curves. The rapid preparation of samples and the short run-time make this method attractive for use in clinical practice.

A "steroid-free" tacrolimus and low-dose mycophenolate mofetil primary immunosuppression does not prevent early acute rejection after liver transplantation.

To assess the efficacy and safety of a primary immunosuppressive regimen with tacrolimus (Tac) and low-dose mycophenolate mofetil (MMF) without steroids and to determine the exposure to mycophenolic acid (MPA) in the early postoperative period, we performed a single-center, randomized 1:1, open-label, controlled study planned to be 60 liver transplantation patients randomized into 2 groups: group A, tacrolimus + MMF (750 mg orally twice a day); and group B, tacrolimus + MMF (750 mg orally twice a day) + steroids. After an interim analysis by the ethical committee patient enrollment was stopped. Data from 30 patients (12 in group A and 18 in group B with a mean follow-up period of 31 +/- 7 months) showed a patient survival rate of 91.7% in group A and 100% in group B and a graft survival rate of 91.7% and 88.9%, respectively. Nine patients (75%) in group A suffered an acute rejection episode, whereas in group B only 3 patients (16.7%) showed acute rejection (P = .002). All rejection episodes occurred in both groups at 1 week after transplantation. The difference in histological grading was statistically significant (P = .021). The toxicity profiles were similar in both groups. A primary immunosuppressive regimen based on Tac and low-dose MMF without steroids is safe but unable to prevent acute rejection at 1 week after transplantation even if early acute rejection does not affect the outcome in terms of morbidity and graft or patient survival.

Disposition of high-dose busulfan in pediatric patients undergoing bone marrow transplantation.

We studied the pharmacokinetics of busulfan (16 mg/kg) in 16 pediatric patients affected by malignant and nonmalignant disorders between 6 months and 19 years of age (mean +/- SD, 5.7 +/- 6.5 years) who were undergoing allogenic (15 patients) and autologous (one patient) bone marrow transplantation. In all children, the conditioning regimen consisted of busulfan given orally at a dose of 1 mg/kg every 6 hours for 16 doses (total dose, 16 mg/kg), associated with other drugs. The pharmacokinetics of busulfan was studied during the 6-hour dosing interval on the third day of therapy by use of a high-performance liquid chromatographic assay. The value for the time to reach maximum concentration, expressed as mean +/- SD, was 1.1 +/- 0.5 hour; maximum concentration was 609.6 +/- 225.3 ng/ml; steady-state concentration was 358.9 +/- 135.5 ng/ml; area under the plasma concentration-time curve was 2153.6 +/- 813.1 ng.hr/ml; oral clearance was 0.535 +/- 0.226 L/hr/kg; and half-life was 2.4 +/- 0.8 hours. Age-related differences in busulfan disposition were observed. The mean busulfan oral clearance in a group of 10 patients with an age range from 6 months to 3 years was 0.619 L/hr/kg, whereas six patients whose ages ranged from 7 to 19 years had a oral clearance of 0.396 L/hr/kg. The half-lives for busulfan during infancy decrease continuously until early childhood but were prolonged in older children. No significant relationship between systemic exposure to busulfan and drug effect was observed.

Combined immunosuppressive therapy with tacrolimus and mycophenolate mofetil for small bowel transplantation in pigs.

In a swine model of orthotopic small bowel transplantation, we assessed the efficacy of combined therapy with a low dose of tacrolimus plus mycophenolate mofetil, compared with high-dose tacrolimus monotherapy. The bowel was replaced in 25 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 10), tacrolimus, 0.3 mg/kg daily i.m. for 7 days, followed by b.i.d. oral doses to maintain blood levels of 15-25 ng/ml; and group 3 (n = 10), tacrolimus, 0.1 mg/kg i.m., in a single dose on day 0 and thereafter oral doses to maintain blood levels of 5-15 ng/ml, plus oral mycophenolate mofetil (10 mg/kg twice daily). Follow-up time was limited to 60 days. Median survival time as 11, 27, and > 60 days in groups 1, 2, and 3, respectively (P = 0.001). Survival rates were 0%, 40%, and 80% at 30 days and 0%, 0%, and 70% at 60 days in groups 1, 2, and 3, respectively (P = 0.03), group 1 vs. group 2; P = 0.003, group 1 vs. group 3; P = 0.02, group 2 vs. group 3). One animal in group 1 (20%) and two animals each in groups 2 and 3 (20%) died of technical complications. Rejection was the cause of death of 80% of animals of group 1 and of no animals in either group 2 or 3. None of the immunosuppressed animals developed clinical or histopathological evidence of graft-versus-host disease. Sixty percent of animals in group 2 (n = 6) and 10% in group 3 (n = 1) died from infections; two other animals in group 2 died of emaciation. The seven animals of group 3 that were alive at 60 days had immunosuppression stopped at that time. All died of rejection within 1 month. In conclusion, double-drug therapy with tacrolimus and mycophenolate mofetil consistently allowed extended survival after small bowel transplantation in swine, preventing or controlling acute cellular rejection without a high incidence of lethal complications related to overimmunosuppression.

Clinical pharmacokinetics of tretinoin.

Recent reports of the dramatic antitumour effect of tretinoin (all-trans retinoic acid) in patients with acute promyelocytic leukaemia (APL) have generated a great deal of interest in the use of this drug as a chemopreventive and therapeutic agent. However, the biological efficacy of tretinoin is greatly impaired by (presumably) an induced hypercatabolism of the drug leading to reduced tretinoin sensitivity and resistance. Several pharmacokinetic studies have shown that plasma drug exposure [as measured by the plasma area under the concentration-time curve (AUC infinity)] declines substantially and rapidly when the drug is administered in a long term daily tretinoin regimen. These observations led to the hypothesis that the rapid development of acquired clinical resistance to tretinoin may have a pharmacological basis and result from an inability to present an effective drug concentration to the leukaemic cells during continuous treatment. The principal mechanisms proposed to explain the increased disappearance of tretinoin from plasma include: (i) decreased intestinal absorption; (ii) enhanced enzymatic catabolism; and (iii) the induction of cytoplasmic retinoic acid binding proteins (CRABP), which leads to increased drug sequestration. The most favoured explanation is that continuous tretinoin treatment acts to induce drug catabolism by cytochrome P450 (CYP) enzymes. Several strategies aimed at preventing or overcoming induced tretinoin resistance have been, and are being, planned. These strategies include intermittent dose administration, administration of pharmacological inhibitors of CYP oxidative enzymes, combination with interferon-alpha and intravenous administration of liposome-encapsulated tretinoin. As these strategies are now under investigation and the number of patients enrolled is small, further studies are needed to determine the efficacy and toxicity of these new schedules of drug administration. In this article we provide an overview of the relevant aspects of tretinoin physiology and pharmacokinetics, and summarise the current status of knowledge to help in the better optimisation of tretinoin administration.

Clinically significant drug interactions with cyclosporin. An update.

Since its approval in 1983 for immunosuppressive therapy in patients undergoing organ and bone marrow transplants, cyclosporin has had a major impact on organ transplantation. It has significantly improved 1-year and 2-year graft survival rates, and decreased morbidity in kidney, liver, heart, heart-lung and pancreas transplantation. Several studies have supported the efficacy of cyclosporin in preventing graft-versus-host disease in bone marrow transplantation. Cyclosporin is also possibly effective in treating diseases of autoimmune origin and as an antineoplastic agent. The introduction of therapeutic drug monitoring of cyclosporin was extremely useful because of the wide inter- and intraindividual variability in the pharmacokinetics of cyclosporin after oral or intravenous administration. Optimal long term use of cyclosporin requires careful monitoring of the blood (or plasma) concentrations. Sustained and clinically significant drug-drug interactions can occur during long term therapy with cyclosporin. The coadministration of multiple drugs with cyclosporin could result in graft rejection, renal dysfunction or other undesirable effects. Any interaction that leads to modified cyclosporin concentrations is of potential clinical importance. Cyclosporin itself may have significant effects on the pharmacokinetics and/or pharmacodynamics of coadministered drugs, such as digoxin, HMG-CoA reductase inhibitors and antineoplastic drugs affected by multidrug resistance. Many drugs have been shown to affect the pharmacokinetics and/or pharmacodynamics of cyclosporin. Interactions between cyclosporin and danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, metoclopramide, nicardipine, verapamil, carbamazepine, phenobarbital (phenobarbitone), phenytoin, rifampicin (rifampin) and cotrimoxazole (trimethoprim/sulfamethoxazole) are well documented in a large number of patients. Other interactions (such as those with aciclovir, estradiol and imipenem) are documented only in isolated case studies.

Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV.

OBJECTIVE: To compare the plasma pharmacokinetics of lamivudine 150mg twice daily and 300mg once daily in patients with HIV-1 infection. DESIGN: Nonblind, sequential, pharmacokinetic study. PARTICIPANTS: 13 patients with HIV-1 infection (median age 36 years). METHODS: Patients were tested during twice daily and then once daily regimens of lamivudine. In both regimens, the total daily dose of lamivudine was identical (300 mg/day). Blood samples for pharmacokinetic analysis were taken over a 12-hour period after > or =7 days of twice daily administration, and again over a 24-hour period after 7 days of once daily administration,. RESULTS: 12 patients completed the study. Lamivudine pharmacokinetic parameters (mean +/- SD) after administration of 150mg twice daily were: peak plasma concentration (Cmax) 2077+/-816 microg/L; trough plasma concentration (Cmin) 332+/-219 microg/L; elimination half-life (t 1/2beta) 6.1+/-1.9h; time to Cmax (t(max)) 1.6+/-0.7h; average concentration over the dosage interval (Cav) 711+/-269 microg/L; and area under the concentration-time curve (AUC) over 2 dosage intervals (24h) 17085+/-6464 microg x h/L. Corresponding values after administration of 300mg once daily were: Cmax 3461+/-854 microg/L; Cmin 146+/-87 microg/L; t1/2 7.9+/-3.4h; t(max) 2.2+/-1.3h; Cav 705+/-177 microg/L; and AUC over 1 dosage interval (24h) 16644+/-4150 microg x h/L. Statistical analysis showed a significant difference (p < 0.05) between the 2 schedules for Cmax and Cmin values, whereas no significant differences emerged for the other parameters. CONCLUSIONS: Once daily lamivudine leads to a similar exposure in plasma as twice daily administration of the same total daily dose. Since once daily administration may result in improved compliance, these results provide the pharmacokinetic basis for using lamivudine in a once daily regimen. Randomised clinical studies are needed to confirm this pharmacokinetic finding.

FK506 effectiveness in reducing acute rejection after heart transplantation: a prospective randomized study.

BACKGROUND: Tacrolimus (FK506) has recently become available clinically as an alternative to cyclosporine-based immunosuppression. This study reports the middle-term results of a prospective, randomized trial that compared FK506 with cyclosporine-based immunosuppression in heart transplant recipients. METHODS: Twenty-five consecutive patients were randomized at a 2:1 ratio into two groups, one of which received FK506 (15 patients), the other cyclosporine (10 patients). Both groups received similar concomitant immunosuppression. The patients were followed up for 12 months. The following outcome parameters were analyzed: survival, rejection and infection rate, lymphocyte subsets, new-onset diabetes, renal and hepatic function, hypertension, right-sided heart catheterization data, graft coronary artery disease, and neurologic side effects. RESULTS: The mortality rate (two patients) in the FK506 group was 13% versus 0% in the cyclosporine group (p = NS). The two deaths were the consequences of early infections and higher doses of FK506. From the outset, the FK506 group presented a lower prevalence of acute rejection, a lower requirement for rejection treatments and a higher incidence of infections. Accordingly, we reduced overall immunosuppression for the last seven patients in the FK506 group; the decrease in FK506 and prednisone dosage led to a decrease in the early infection rate without an increase in the rejection rate. There was no difference between the two groups in diabetes incidence, renal and hepatic function, right-sided heart catheterization data, or coronary angiograms. Hypertension was less frequent and milder in the FK506 group. CONCLUSIONS: This experience suggests that FK506 can be safely used in heart transplantation. It can decrease the frequency of rejection episodes. Low-dose administration allows a lower infection rate without an increase in rejection. With a protocol of delayed starting and low dosing, side effects such as renal toxicity, hypertension, and neurologic toxicity seem to be unlikely. Further studies are needed to establish the exact dosage and therapeutic levels of the drug.

A model of in vivo purging with Rituximab and high-dose AraC in follicular and mantle cell lymphoma.

We studied a model of in vivo purging with Rituximab and high-dose (HD) cytarabine in 14 patients with relapsed/refractory follicular lymphoma and two with refractory mantle cell lymphoma enrolled in a program of HD chemotherapy and autotransplant. After two courses of debulking immunochemotherapy with Rituximab, Vincristine and Cyclophosphamide, we used a combination of Rituximab, HD cytarabine and granulocyte colony-stimulating factor for peripheral blood stem cells (PBSC) mobilization. The median number of CD34+ cells collected was 14.69 x 10(6)/kg (range 5.74-73.2). Monitoring of peripheral CD19+ and CD20+ B cells prior to and throughout the purging period showed that a treatment with Rituximab, Vincristine and Cyclophosphamide results in a profound depletion of B cells in peripheral blood. B-cell depletion persists during mobilization with Rituximab and HD cytarabine allowing a collection of PBSC free of B cells (median CD19+ and CD20+ cells counts 0%). Of nine patients PCR positive for bcl-2 or bcl-1 in blood and marrow at the start of immunochemotherapy, all showed PCR-negative PBSC. In conclusion, in patients with indolent lymphoma, the concurrent administration of Rituximab and HD cytarabine is a safe and efficient method to obtain in vivo purged PBSC. Immunochemotherapy prior to mobilization produces B-cell depletion and seems to be a useful preparative step.

Optimization of sampling time for cyclosporine monitoring in transplant patients.

Cyclosporine (CsA) dosing is based on CsA plasma or blood concentrations measured 12 to 24 hours after drug administration (trough levels). This study evaluated the relationship between the timing of CsA concentrations and subsequent pharmacokinetic parameters to predict an optimal sampling period. Plasma samples were obtained from 22 patients before their morning dose of CsA and at 2, 4, 6, 8, 10, and 12 hours after the dose on the 7th and on the 21st day after heart transplantation. The plasma samples were assayed by both HPLC and FPIA. The Cmax for CsA was achieved over a period ranging from 2 to 6 hours (mean/median = 4.7/4.0) during the day 7 and the day 21 studies. The mean (+/- SD) half-life was 3.2 (1.0) hours on day 7 and 2.9 (1.1) hours on day 21, (P > 0.05); the mean apparent oral clearance was 276 (117) L/hr on the day 7 and 269 (209) L/hr on day 21, (P > 0.05). When CsA plasma concentration by either FPIA and HPLC was monitored, the drug concentration best correlated with AUC was found to correspond to the plasma samples taken 4 to 8 hours after drug administration. The authors conclude that through blood sampling for therapeutic drug monitoring of CsA is not optimal, and that further studies are necessary to correlate concentration monitoring during the dosing interval with pharmacologic and toxicologic parameters.

Pharmacokinetics of hydroxyurea in patients infected with human immunodeficiency virus type I.

In a prospective, randomized, controlled, three-arm study, the pharmacokinetics of hydroxyurea administered as an antiviral agent in patients infected with human immunodeficiency virus type 1 (HIV-1) were evaluated. The three arms of the study consisted of azidothymidine (AZT) 250 mg twice daily, hydroxyurea 500 mg twice daily, or a combination of the two. Nine patients receiving hydroxyurea in monotherapy (n = 4) or in combination with AZT (n = 5) agreed to undergo multiple venipunctures for pharmacokinetic analysis. Sample collection was performed at steady-state conditions and serum concentration-time data for hydroxyurea were fitted using a one-compartment model. Mean (+/- standard deviation) peak concentration (Cmax) was 0.135 +/- 0.06 mmol/L and mean trough level (Cmin) was 0.0085 +/- 0.003 mmol/L. Mean concentration at steady state was 0.045 +/- 0.006 mmol/L. Apparent clearance (Cl/F) was 0.18 +/- 0.005 L/hr/kg, and half-life (t1/2) was 2.5 +/- 0.5 hours. Hydroxyurea given orally to patients infected with HIV-1 was well absorbed from the gastrointestinal tract, with a tmax of 0.85 to 0.96 hours after ingestion. Serum levels of hydroxyurea ranged from 0.01 to 0.13 mmol/L. These values are similar to the concentrations (between 0.01 and 0.1 mmol/L) demonstrated to inhibit HIV-1 in vitro. Our data show that hydroxyurea given at a dosage of 500 mg twice daily is sufficient to yield serum concentrations potentially useful for in vivo inhibition of HIV-1.

Clinical relevance of all-trans retinoic acid pharmacokinetics and its modulation in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA) which exerts its action via a well-documented cytodifferentiating mechanism. The combination of this retinoid with anthracyclines gives high percentages of complete remission and is now considered the optimal induction treatment for APL patients. Continuous treatment with ATRA, however, induces accelerated drug catabolism, with progressive decline in plasma drug concentrations potentially to below the levels required to maintain differentiation of leukemic cells. This process, which occurs rapidly and consistently has led to the hypothesis that the development of acquired clinical resistance to ATRA in APL has a pharmacologic basis. The rapid autoinduction of the hypercatabolic state precludes maintenance with continuous ATRA oral dosing, and is a limitation of better use of the drug both in APL and in other disorders in which it could be beneficial. Here we briefly review the pharmacologic alterations of ATRA metabolism induced by continuous oral administration, the clinical implications of this phenomenon, and the strategies currently under investigation to prevent or overcome the induced catabolism of this retinoid.

Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto di Midollo Osseo).

Busulfan (BU) is an alkylating drug frequently used to prepare patients for bone marrow transplantation (BMT). Several studies have documented that there is important interpatient variability in BU disposition and systemic exposure, and that other drugs with a common metabolic pathway are capable of influencing BU clearance. We compared the BU pharmacokinetics and pharmacodynamics of 13 patients given BMT and receiving BU and itraconazole, with those of 26 matched controls who did not receive any anti-fungal agent, and with those of 13 matched patients treated with fluconazole as prophylaxis against fungal infections. The effect of itraconazole was best reflected in BU clearance since the BU dose was modified in some patients. BU clearance was decreased by an average of 20% in patients receiving itraconazole as compared to control patients and patients receiving fluconazole (p < 0.01). Mean BU clearance was 7.653 +/- 1.871 l/hr.m2 in the itraconazole patients, 10.103 +/- 2.007 l/hr.m2 in the fluconazole group and 9.373 +/- 1.702 l/hr.m2 in the control group. In this study itraconazole, but not fluconazole, markedly affected the pharmacokinetics of BU as an increase of BU plasma concentrations was observed. The nature of this interaction has not yet been fully characterized. Itraconazole and its analogues are inhibitors of both cytochrome P450 and lipoxygenase and since itraconazole can modulate BU pharmacokinetics, oxidative catabolism is probably a determinant of BU metabolism. This hypothesis should be tested in human metabolic studies.