Pharmacokinetics of low-dose protease inhibitors and efavirenz in low- and middle-income countries.

Item does not contain fulltextPURPOSE OF REVIEW: The costs associated with antiretroviral therapy are becoming a major concern for the treatment of HIV-infected patients in resource-limited countries. Potential risk for the increase in toxicity due to higher drug exposure among Asians is also a concern. In this article, we discuss the studies performed using low-dose antiretroviral therapy as an effective and well tolerated strategy. RECENT FINDINGS: The studies reviewed demonstrate that dose reduction of antiretroviral therapy provides adequate plasma concentrations and effective immunological and virological responses in, mainly, a Thai population compared with whites. The differences in these pharmacokinetic parameters could possibly be due to differences in body weight and composition, drug-food interactions, metabolism, environmental factors and genetic background. Moreover, dose reduction can possibly decrease toxicity and save costs for patients in low- and middle-income countries. SUMMARY: Although the use of low-dose antiretroviral drugs showed adequate plasma levels in an Asian population, in particular, careful attention has to be given to pharmacokinetic, safety and efficacy data to avoid problems of subtherapeutic levels and drug resistance. Large, phase III studies are warranted.1 januari 201

Solubility of Gases in Liquids. 17. The Solubility of He, Ne, Ar, Kr, H\u3csub\u3e2\u3c/sub\u3e, N\u3csub\u3e2\u3c/sub\u3e, O\u3csub\u3e2\u3c/sub\u3e, CO, CH\u3csub\u3e4\u3c/sub\u3e, CF\u3csub\u3e4\u3c/sub\u3e, and SF\u3csub\u3e6\u3c/sub\u3e in Tetrachloromethane at 283-318 K

The Ostwald coefflclents L2,1( T,P) of He, Ne, Ai, Kr, H2, N2, O2, CO, CH4, CF4, and SF6 in tetrachloromethane have been determined at about atmospheric pressure, and from 283 to 318 K, by a modified Ben-Nalm/Baer apparatus

Involvement of intracellular calcium stores in Giardia lamblia induced diarrhoea in mice

The transmucosal fluxes of Na+ and Cl- were studied in Giardia lamblia-infected mice in the presence of absence of dantrolene (1-(5(p-nitrophenyl)furfurilidene-amino) hydantoinsodiumhydrate). There was net secretion of Na+ and Cl- in infected animals, while in control animals there was net absorption of these ions. The addition of dantrolene resulted in significant net increase in absorption of Na+ and Cl- in control and experimental groups. Further, mouse intestinal epithelial cells were labelled with [32P]Pi and then treated with G. lamblia trophozoites and their excretory secretory products separately. The optimum time for inositol triphosphate formation was 15 min in control enterocytes as well as in treated enterocytes. A plateau was formed at higher concentrations. Since raised inositol triphosphate levels mobilize Ca2+ from intracellular stores and dantrolene traps Ca2+ within intracellular calcium stores, the present study thus suggests that intracellular calcium stores are involved in G. lamblia-induced diarrhoea in mice

Solubility of Gases in Liquids. 17. The Solubility of He, Ne, Ar, Kr, H\u3csub\u3e2\u3c/sub\u3e, N\u3csub\u3e2\u3c/sub\u3e, O\u3csub\u3e2\u3c/sub\u3e, CO, CH\u3csub\u3e4\u3c/sub\u3e, CF\u3csub\u3e4\u3c/sub\u3e, and SF\u3csub\u3e6\u3c/sub\u3e in Tetrachloromethane at 283-318 K

The Ostwald coefflclents L2,1( T,P) of He, Ne, Ai, Kr, H2, N2, O2, CO, CH4, CF4, and SF6 in tetrachloromethane have been determined at about atmospheric pressure, and from 283 to 318 K, by a modified Ben-Nalm/Baer apparatus

Pharmacokinetics and 48 Week Efficacy of Adjusted Dose Indinavir/Ritonavir in Rifampicin-Treated HIV/Tuberculosis-Coinfected Patients: A Pilot Study

Contains fulltext : 109029.pdf (publisher's version ) (Closed access)Abstract HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/mul. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure

Low dose lopinavir/ritonavir tablet achieves adequate pharmacokinetic parameters in HIV-infected Thai adolescents.

Item does not contain fulltextBACKGROUND: Lopinavir/ritonavir (LPV/r) is an effective and commonly used protease inhibitor in HIV-infected adolescents. Previous data showed high plasma concentrations of LPV in Thai patients. This study determined the pharmacokinetic (PK) parameters of a low-dose LPV/r tablet (70% of standard dose) in HIV-infected Thai adolescents. METHODS: A total of 24 adolescents on LPV/r-containing HAART regimens with HIV RNA35 kg, respectively. On the fourth week of treatment, PK was performed for all doses at 0 (pre-dose), 2, 4, 6, 8, 10 and 12 h. LPV and ritonavir concentrations were measured using the HPLC method. RESULTS: The median (IQR) age was 13.5 (12-15) years. The median LPV doses of standard and low doses were 290 and 208 mg/m(2). The mean (sd) area under the concentration-time curve at 0-12 h, maximum concentration and plasma concentration at 12 h for the standard dose were 97.6 (25.7) mg*h/l, 11.1 (2.6) mg/l and 4.1 (2.0) mg/l, and for the low dose were 87.4 (29.0) mg*h/l, 11.0 (3.1) mg/l and 3.2 (1.9) mg/l, respectively. No significant differences were detected between the groups. One child had plasma concentration at 12 h <1.0 mg/l while on low-dose LPV/r but HIV RNA was undetectable. CONCLUSIONS: The low-dose LPV/r tablet provides adequate PK parameters in HIV-infected Thai adolescents. A randomized study to assess the efficacy of low and standard doses of LPV/r among Thai HIV-infected adolescents should be explored

Plasma concentrations of generic lopinavir/ritonavir in HIV type-1-infected individuals.

Contains fulltext : 81956.pdf (publisher's version ) (Closed access)BACKGROUND: Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation. METHODS: In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups. RESULTS: A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients. CONCLUSIONS: The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries

Pharmacokinetics of and short-term virologic response to low-dose 400-milligram once-daily raltegravir maintenance therapy.

Because studies showed similar viral suppression with lower raltegravir doses and because Asians usually have high antiretroviral concentrations, we explored low-dose raltegravir therapy in Thais. Nineteen adults on raltegravir at 400 mg twice daily (BID) with HIV RNA loads of <50 copies/ml were randomized to receive 400 mg once daily (QD) or 800 mg QD for 2 weeks, followed by the other dosing for 2 weeks. Intensive pharmacokinetic analyses were performed, and HIV RNA was monitored. Two patients were excluded from the 400-mg QD analysis due to inevaluable pharmacokinetic data. The mean patient weight was 58 kg. Mean pharmacokinetic values were as follows: for raltegravir given at 400 mg BID, the area under the concentration-time curve from 0 to 12 h (AUC(0)(-)(1)(2)) was 15.6 mg/liter-h and the minimum plasma drug concentration (C(trough)) was 0.22 mg/liter; for raltegravir given at 800 mg QD, the AUC(0)(-)(2)(4) was 33.6 mg/liter-h and the C(trough) was 0.06 mg/liter; and for raltegravir given at 400 mg QD, the AUC(0)(-)(2)(4) was 18.6 mg/liter-h and the C(trough) was 0.08 mg/liter. The HIV RNA load was <50 copies/ml at each dose level. Compared to the adjusted AUC(0)(-)(2)(4) for Westerners on raltegravir at 400 mg BID, Thais on the same dose had double the AUC(0)(-)(2)(4) and those on raltegravir at 400 mg QD had a similar AUC(0)(-)(2)(4). More patients had a C(trough) of <0.021 mg/liter on raltegravir at 400 mg QD (9/17 patients) than on raltegravir at 800 mg QD (1/19 patients) or 400 mg BID (0/19 patients). Seventeen patients used raltegravir at 400 mg QD for a median of 35 weeks; two had confirmed HIV RNA loads between 50 and 200 copies/ml, and both had low C(trough) values. Low-dose raltegravir could be a cost-saving option for maintenance therapy in Asians or persons with low body weight. However, raltegravir at 400 mg QD was associated with a low C(trough) and with a risk for HIV viremia. Raltegravir at 200 or 300 mg BID should be studied, but new raltegravir formulations will be needed

Pharmacokinetics and 48-week safety and efficacy of generic lopinavir/ritonavir in Thai HIV-infected patients

Item does not contain fulltextBACKGROUND: Generic products reduce the costs of HIV treatment. Few generic second-line antiretroviral products are available. We assessed pharmacokinetics, safety and efficacy of generic lopinavir/ritonavir (LPV/r) produced by the Government Pharmaceutical Organization (GPO) of Thailand in Thai HIV-infected adults. METHODS: This was a single-arm prospective study. Patients with plasma HIV-1 RNA/=24 weeks, who were protease inhibitor (PI)-naive or experienced, were eligible. Patients started generic LPV/r tablets, 400/100 mg twice daily. At week 4, therapeutic drug monitoring was performed and analysed by validated HPLC. In patients using Kaletra((R)) (Abbott Laboratories, North Chicago, IL, USA) soft gel capsules (SGC) or generic LPV/r tablets produced by Mylan (Canonsburg, PA, USA; formerly Matrix, Hyderabad, India) prior to study entry, we compared the plasma minimum concentrations (Cmin) of the different formulations. Plasma HIV-1 RNA and safety were assessed until week 48. RESULTS: A total of 70 patients (32 males) were enrolled. Mean (sd) age was 40.7 (7.9) years and mean (sd) body weight was 60.3 (9.0) kg. Before study entry, all patients were virologically suppressed using a PI-based regimen; 62 (88.6%) were using LPV/r (Kaletra((R)) SGC n=22 and Mylan generic tablets n=40). Mean (sd) Cmin of GPO lopinavir and GPO ritonavir at week 4 were 7.1 (2.9) mg/l and 0.39 (0.21) mg/l, respectively, and not significantly different from the Cmin when taking Kaletra((R)) SGC or Mylan generic tablets. After 48 weeks, 95.6% of patients maintained plasma HIV-1 RNA<50 copies/ml. Four grade 3 and no grade 4 adverse events were reported. CONCLUSIONS: Generic LPV/r showed adequate levels, good tolerability and excellent 48-week efficacy