Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses

The pharmacokinetics and short-term safety of atazanavir 150 and 200 mg, when coadministered with saquinavir/ritonavir 1600/100 mg once daily, were evaluated. On day 1, atazanavir 150 mg once daily, was added to saquinavir/ritonavir regimens and sampling was performed to evaluate saquinavir, ritonavir, and atazanavir pharmacokinetics (day 11). Atazanavir was increased to 200 mg and pharmacokinetic assessment repeated (day 30). Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir, ritonavir, and atazanavir pharmacokinetic parameters in the present study and for 14 of the subjects treated with saquinavir/ritonavir 1600/100 mg once daily without and with atazanavir 300 mg who participated in a previous trial. Geometric mean (GM) saquinavir AUC0-24, Ctrough, and Cmax were 30,589 and 32,312 ng . h/ml, 166 and 182 ng/ml, and 4267 and 4261 ng/ml when coadministered with atazanavir 150 and 200 mg (n = 18). On days 11 and 30, saquinavir and atazanavir Ctrough remained >100 ng/ml in 13/18, 14/18, 18/18, and 17/18 patients. Among the above mentioned 14 subjects, significant increases in saquinavir Ctrough (87%, 92%, 99%), Cmax (40%, 55%, 44%), and AUC0-24 (51%, 60%, 63%) were observed with atazanavir 300, 150, and 200 mg. Ritonavir AUC0-24 and Cmax were significantly increased with the addition of atazanavir 300 mg only. Atazanavir enhances saquinavir and ritonavir by a mechanism that requires elucidation. While saquinavir enhancement was apparently independent of atazanavir dose, atazanavir 300 mg produced an increase in ritonavir Cmax, which is not observed with lower atazanavir doses. Atazanavir-related hyperbilirubinemia was dose dependent. However, higher saquinavir and atazanavir exposure may be required to suppress HIV-resistant strain replication.     

Lopinavir/ritonavir plus saquinavir in salvage therapy; pharmacokinetics,tolerability and efficacy

Patients receiving a lopinavir/ritonavir and saquinavir dual protease inhibitor-based antiretroviral salvage regimen were studied to evaluate the pharmacokinetics, tolerability and efficacy of the regimen. Pharmacokinetic curves were obtained for lopinavir and saquinavir. Patient records were studied for adverse events and efficacy data. The pharmacokinetics of lopinavir and saquinavir were comparable with literature data, except for the saquinavir 0-12 h area under the curve and maximum concentration. The tolerability of the regimen was good and efficacy was encouraging.     

Steady-state pharmacokinetics of once-daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteers

OBJECTIVES: Use of proton pump inhibitors in HIV-infected patients is common. The purpose of this study was to determine the steady-state pharmacokinetics of once-daily (qd) fosamprenavir/ritonavir (FPV/r) and atazanavir/ritonavir (ATV/r) alone and in combination with 20 mg qd omeprazole (OMP) in healthy volunteers. DESIGN AND METHODS: A prospective, open-label, single-site, two-period, crossover pharmacokinetic study was carried out in healthy volunteers. Subjects received either qd FPV/r 1400 mg/200 mg or ATV/r 300 mg/100 mg in the morning for 14 days and then 20 mg OMP in the evening for an additional 7 days. The pharmacokinetics were assessed over 24 h on days 14 and 21. Following a 2-week washout, subjects repeated the process with the other regimen. Trough protease inhibitor (PI) concentrations were taken on day 16 of each period to assess the impact of a single dose of OMP on ATV and amprenavir (APV) concentrations. Plasma ATV and APV pharmacokinetic parameters were assessed by noncompartmental analysis; geometric mean ratios (GMRs; PI+OMP/PI; 90% confidence interval) were calculated between days 14 and 21. RESULTS: Nineteen healthy, non-HIV-infected volunteers were evaluated. OMP reduced ATV exposure [area under the concentration curve at 0-24 h (AUC0-24 h)] and the minimum drug concentration (Cmin) by 27% each. In contrast, APV exposure and Cmin were decreased by 4 and 2%, respectively. Four subjects (21%) experienced greater than 50% declines in both ATV AUC0-24 h and Cmin after the addition of OMP; this was not observed in any subject following receipt of FPV/r. No alterations in APV or ATV trough concentrations were observed following a single dose of OMP. CONCLUSIONS: The addition of 20 mg OMP administered in the evening has minimal effect on APV pharmacokinetics. In contrast, ATV pharmacokinetics were altered; a number of ATV-treated subjects experienced pronounced declines in exposures upon the addition of 20 mg OMP administered in the evening, whereas others experienced little to no change.     

Efficacy, tolerance, and pharmacokinetics of the combination of stavudine, nevirapine, nelfinavir, and saquinavir as salvage regimen after ritonavir or indinavir failure

The high rate of protease inhibitor treatment failure in clinical cohorts makes it necessary to define novel salvage therapies. In a prospective study of 31 HIV-infected patients included in a salvage regimen with stavudine, nevirapine, nelfinavir, and saquinavir, viral load decreased a median of 1.65 log(10) and 1.95 log(10) after 6 and 12 months of treatment, respectively, and 35 and 56% of patients had an HIV RNA level below 50 copies/ml at the same time points. At baseline, the mean number of mutations in the protease gene was 10 (2-19), and the V82A and L90M mutations were present in 54 and 21% of patients. The presence of the V82A mutation did not affect significantly the rate of response (36 vs. 38%), whereas the L90M mutation was associated with treatment failure (0 vs. 43%). Plasma trough levels of nelfinavir (NFV) and saquinavir (SQV), in a twice daily dosing regimen, were above the protein-corrected IC(95) in most patients despite the addition of an enzymatic inducer such as nevirapine, and peak levels were 2- and 5-fold increased with respect to standard doses. However, pharmacokinetics of saquinavir-hard gel capsule (SQV-hgc) did not improve significantly in the three times daily dosing regimen. In conclusion, the combination of stavudine, nevirapine, nelfinavir, and saquinavir increased plasma drug levels and produced an adequate virological response in patients who had failed indinavir or ritonavir therapy. This degree of response is not significantly decreased in the presence of genotypic mutations associated with indinavir/ritonavir (IDV/RTV) resistance.     

Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers

Objective

To evaluate the pharmacokinetics and safety of a boosted saquinavir (SQV)/ritonavir (RTV) combination, administered as either the hard gelatin capsule (HGC) or soft gelatin capsule (SGC) formulation of SQV, in 24 healthy volunteers.

Methods

This was a single‐centre, open‐label, randomized, 2 × 2 crossover study. Twelve subjects were randomized to receive SQV/RTV 1000 mg/100 mg twice daily (BID) orally for 10 days, as either the HGC or SGC formulation. The pharmacokinetic profile of SQV was determined on day 10. Subjects then crossed over to the opposite SQV formulation, and the pharmacokinetic profile was determined again on day 20. The primary analysis was the assessment of bioequivalence based on logarithmically transformed values for AUC_{(0?24 h)} and C_max for the two formulations.

Results

There was a statistically significant increase in the geometric means of all the pharmacokinetic variables evaluated for SQV‐HGC/RTV compared with SQV‐SGC/RTV. A mean AUC_{0?24 h}‐value of 15.798 µg/mL/h was reported for the HGC formulation compared with 11.655 µg/mL/h for the SGC formulation (P = 0.0043). The SQV‐HGC/RTV combination was better tolerated in terms of gastrointestinal system disorders. Furthermore, no elevations in triglycerides or total cholesterol were reported with SQV/RTV during the entire study period.

Conclusion

In healthy volunteers, RTV boosting of SQV‐HGC produces plasma exposures at least comparable to SQV‐SGC, which is accompanied by an improvement in gastrointestinal system disorders.

     

Combined therapy with saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed HIV-infected protease inhibitor-naive patients

¹ Basel Centre for HIV Research, Outpatient Department of Internal Medicine, University Hospital Basel, ² Department of Internal Medicine, Cantonal Hospital St Gallen, ³ Department of Internal Medicine, Regional Hospital Lugano, ⁴ Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, ⁵ Basel Centre for HIV Research, Institute for Medical Microbiology, University Basel, ⁶ Division of Infectious Diseases, University Hospital Bern, ⁷ Division of Infectious Diseases, University Hospital Lausanne, ⁸ Roche Pharma AG, Reinach, and ⁹ Division of Infectious Diseases, University Hospital Geneva, Switzerland Objective To assess the short‐term and long‐term effect of a combination of saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed protease inhibitor‐naive patients. Design Prospective open‐label multicentre study. Patients and Methods A total of 64 protease inhibitor‐naive and stavudine‐naive HIV‐infected patients with a CD4 count of < 250 cells/μL and > 10 000 HIV‐1 RNA copies/mL received saquinavir hard‐gelatin capsules, ritonavir and stavudine. Full (drop in viraemia of > 2 log₁₀ and/or < 500 copies/mL) and partial responders (drop to between 500 and 5000 viraemia copies/mL) at week 9 (end of phase I) entered the second phase (additional 12‐month period). Results Fifty‐six patients completed phase I, 45 (70%) full responders and nine (14%) partial responders by intent‐to‐treat analysis. Thirty‐nine patients completed phase II, 33 (52%) full responders and two (3%) partial responders. Six patients had < 50 HIV‐1 RNA copies/mL at week 9, and 20 (31%) patients at month 12 of phase II. Mean CD4 cell counts increased significantly in the 56 patients from 89 to 184 cells/μL after 9 weeks and from 100 to 292 cells/μL in the 39 patients treated for another 12 months. Higher baseline viraemia and lower baseline CD4 cell counts were not associated with an unfavourable virological response at week 9 and month 12 of phase II. HIV DNA in peripheral blood monocytes decreased substantially (? 1.5 log₁₀) but was detectable in all except one patient at the end of phase II. Conclusion In protease‐ and stavudine‐naive HIV‐infected patients with moderate to severe immunosuppression, saquinavir in combination with ritonavir and stavudine caused a substantial long‐term decrease in plasma viral load in approximately half the participants and a substantial increase in CD4 cell counts.     

Comparison of sulfamethoxazole alone and combined with trimethoprim in urinary tract infections

Summary In a double blind, randomized study, sulfamethoxazole was compared alone and in combination with trimethoprim as commonly used in therapeutic regimes for the treatment of uncomplicated acute urinary tract infections in outpatients. The cure rate of sulfamethoxazole alone was 92.2%, and for sulfamethoxazole plus trimethoprim 97.6%. The rate of side-effects for the former was 5%, for the latter 21.8%. If the failure rate plus the rate of occurrence of rash, which necessitated discontinuing the drug, are combined, it appears that 8.8% of the patients were at a disadvantage receiving sulfamethoxazole compared to 9.7% for the combination of sulfamethoxazole plus trimethoprim. When considering the cure rate and rate of side-effects together, therefore, the position of sulfamethoxazole alone as a suitable drug in this type of infection is defended.

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Vergleich von Sulfamethoxazol allein und in Kombination mit Trimethoprim bei Harnwegsinfektionen

Zusammenfassung In einer randomisierten Doppelblindstudie wurde Sulfamethoxazol allein und in Kombination mit Trimethoprim, wie es allgemein in Therapieschemata für die Behandlung der unkomplizierten Harnwegsinfektionen gebraucht wird, untersucht. Die Heilungsrate von Sulfamethoxazol allein betrug 92,9% und von Sulfamethoxazol plus Trimethoprim 97,6%. Die Rate an Nebenwirkungen für das erstere betrug 5%, für das letztere 21,8%. Wenn die Versagerraten mit der Rate an Exanthemen kombiniert werden, die ein Absetzen des Medikamentes erforderlich machten, dann sieht es so aus, daß 8,8% der Patienten nachteilige Erfahrungen machten, die Sulfamethoxazol erhielten, verglichen mit 9,7% von denen, die die Kombination von Sulfamethoxazol plus Trimethoprim erhielten. Wenn die Heilungsrate und Nebenwirkungsrate zusammen betrachtet werden, ist die Bedeutung des Sulfamethoxazol allein als geeignetes Medikament für diese Art von Infektionen belegt.

     

Comparison between chemoembolization combined with radiotherapy and chemoembolization alone for large hepatocellular carcinoma

AIM: To investigate the efficacy of transcatheter arterial chemoembolization (TACE) combined with radiotherapy for unresectable large hepatocellular carcinoma (HCC). METHODS: From June 1994 to June 1999, a total of 76 patients with large unresectable HCC were treated with TACE followed by external-beam irradiation. 89 patients with large HCC, who underwent TACE alone during the same period, served as the control group. Clinical features, therapeutic modalities, acute effects and survival rates were analyzed and compared between TACE plus irradiation group and TACE alone group. A multivariate analysis of nine clinical variables and one treatment variable (irradiation) was performed by the Cox proportional hazards model. RESULTS: The clinical features and therapeutic modalities except irradiation between the two groups were comparable (P>0.05). The objective response rate (RR) in TACE plus irradiation group was higher than that in TACE alone group (47.4 % vs 28.1 %, P<0.05). The overall survival rates in TACE plus irradiation group (64.0 %, 28.6 %, and 19.3 % at 1, 3, 5 years, respectively) were significantly higher than those in TACE alone group (39.9 %, 9.5 %, and 7.2 %, respectively, P=0.0001). Cox proportional hazards model analysis showed that tumor extension and Child grade were significant and were independent negative predictors of survival, while irradiation was an independent positive predictor of survival. CONCLUSION: TACE combined with radiotherapy is more effective than TACE alone, and is a promising treatment for unresectable large HCC.     

Nephrotoxicity of ifosfamide, carboplatin and etoposide (ICE) alone or combined with extracorporeal or radiant-heat-induced whole-body hyperthermia

Although whole-body hyperthermia combined with specific genotoxic chemotherapy can be shown to enhance neoplastic cell killing without a concomitant rise in bone marrow toxicity, nephrotoxicity can become treatment-limiting. This study compares the kidney toxicity to the kidney of ifosfamide, carboplatin and etoposide (ICE) chemotherapy alone, and ICE chemotherapy combined with either extracorporeal (e-WBH) or radiant-heat-induced hyperthermia (r-WBH) in 43 patients with refractory sarcoma. Within 3 days of ICE chemotherapy treatment there was a significant increase in urinary protein excretion and a reduction of the glomerular filtration rate. These effects were more pronounced if WBH was added. The use of immunoluminometric assays revealed a predominance of low-molecular-mass proteins. This increase in protein excretion persisted in the e-WBH-treated group, whereas it vanished within 3 weeks in both the group treated with ICE alone and that treated with r-WBH. Our findings suggest that ICE chemotherapy causes transient tubular and glomerular damage, which is enhanced by WBH. In terms of long-term nephrotoxicity e-WBH was more nephrotoxic than r-WBH. This finding is consistent with our clinical observations. Received: 19 April 1999 / Accepted: 7 September 1999     

Methotrexate (NSC-740) with citrovorum factor (NSC-3590) rescue, alone and in combination with cyclophosphamide (NSC-26271), in ovarian cancer.

In a randomized study, 35 patients with advanced-stage epithelial ovarian cancers with progressive disease after prior single alkylating agent or combination-agent chemotherapy were treated with either intermediate high-dose methotrexate-citrovorum factor rescue alone or methotrexate-citrovorum factor rescue plus cyclophosphamide. Objective responses to both "second-line" chemotherapeutic regimens were observed. The objective response rate of 43% observed with the methotrexate-citrovorum factor plus cyclophosphamide treatment was superior to that achieved with methotrexate-citrovorum factor given alone. This combination of agents is the most effective second-line chemotherapeutic regimen for ovarian cancer that we have yet tested and we are therefore optimistic about its possibilities as first-line therapy. After early dosage modifications, serious toxic side effects were rare in this group of patients who had had extensive prior therapy.