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

OBJECTIVE: 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)]. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Therapeutic Drug Monitoring of Indinavir in HIV-Infected Patients Undergoing HAART

Background: Therapeutic drug monitoring (TDM) of protease inhibitors (PI) is gaining increasing importance for the management of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). The PI indinavir (IDV) is widely used in HAART regimens. Combinations of IDV with ritonavir (RTV) have been used to increase the plasma concentration of IDV. However, the desirable IDV concentration range in clinical practice remains to be elucidated. Patients and Methods: To study the value of TDM for IDV in clinical practice, a retrospective analysis of 501 plasma samples of patients treated with IDV in various dosages was performed. IDV levels were determined during routine outpatient visits. Analysis was performed by high pressure liquid chromatography (HPLC) with UV detection. Results: A widespread range of IDV plasma concentrations was seen both within and between patients. The mean IDV level during therapy with IDV 2.4 g/d was 3,260 ng/ml (95% CI: 2,903 ng/ml; 3,618 ng/ml). IDV levels at a dose of IDV 1.6 g/d in combination with RTV resulted in a mean IDV plasma concentration of 4,191 ng/ml (95% CI: 3,356 ng/ml; 5,016 ng/ml). There was no significant difference between plasma levels at the doses of 2.4 g/d and 1.6 g/d. 35 of all 130 patients treated with IDV reached only suboptimal IDV plasma concentrations below the limit of 150 ng/ml. There was no statistically significant difference between the number of patients below an IDV plasma concentration of 150 ng/ml in the various dosage regimens. Conclusion: During therapy with IDV in a b.i.d. scheme, similar IDV plasma concentrations and a comparable number of patients with subinhibitory plasma concentrations were observed when compared to a therapeutic regimen with t.i.d. dosing. In this study, even at various times of plasma sampling after oral ingestion, TCM facilitated the surveillance of patients compliance. Received: August 07, 2000 · Revision accepted: August 27, 2001     

Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy

OBJECTIVE: To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations. DESIGN: The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults. METHODS: Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection. RESULTS: Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008). CONCLUSIONS: The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.     

Measurement and characterization of insulin-like growth factor binding protein-3 in human biological fluids: discrepancies between radioimmunoassay and ligand blotting.

The inability to detect insulin-like growth factor binding protein-3 (IGFBP-3) in some circumstances by Western ligand blot analysis has emphasized the need to characterize IGFBPs by both ligand binding and immunological techniques. In this study, we have: 1) characterized and quantified IGFBP-3 in nonpregnancy, pregnancy, and fetal cord serum, follicular, peritoneal, and amniotic fluid, seminal plasma, cerebrospinal fluid (CSF), and urine; 2) established a new IGFBP-3 RIA that detects both intact and fragments of IGFBP-3; 3) identified both intact and fragments of IGFBP-3 by Western immunoblot techniques; and 4) addressed the discordance between Western ligand blot analysis and RIA by assessing fluids for IGFBP proteolytic activity. All fluids examined, except pregnancy serum, CSF, and amniotic fluid, displayed a 44-34-kilodalton (kDa) IGFBP-3 doublet by Western ligand blot analysis. Western immunoblot analysis using specific IGFBP-3 antiserum showed a 44-34-kDa IGFBP-3 doublet and a 28-kDa fragment in nonpregnancy serum, fetal cord serum, follicular fluid, and peritoneal fluid. The immunoreactive 42-38-kDa doublet was faint in urine and seminal plasma. IGFBPs in CSF did not cross-react with IGFBP-3 antiserum. Pregnancy serum and amniotic fluid contained only the 28-kDa fragment when compared against equal volumes of nonpregnancy serum. With the development of an IGFBP-3 RIA, IGFBP-3 could be accurately measured; urine, CSF, and seminal plasma contained the lowest levels of IGFBP-3 at 27 +/- 3 ng/ml (mean +/- SEM), 110 +/- 26 ng/ml, and 209 +/- 56 ng/ml, respectively. In increasing concentration: fetal cord serum contained 753 +/- 101 ng/ml; peritoneal fluid, 1124 +/- 130 ng/ml; follicular fluid, 2356 +/- 211 ng/ml; nonpregnancy serum, 3556 +/- 508 ng/ml; pregnancy serum, 3718 +/- 842 ng/ml; and amniotic fluid, 5150 +/- 688 ng/ml. The measurable concentrations of IGFBP-3 in CSF and the high concentrations measured in pregnancy serum and amniotic fluid conflicted with Western blot analysis. Thus, fluids were assessed for IGFBP proteolytic activity by incubation with a source of IGFBP-3, either nonpregnancy serum or purified IGFBP-3. All fluids displayed some proteolytic activity with either assay. Fluids with little protease activity (nonpregnancy serum, follicular fluid, and urine) showed a close relationship between immunoassayable IGFBP-3 by RIA and IGFBP-3 band intensity by Western ligand blot. Fluids with high proteolytic activity (pregnancy serum, CSF, seminal plasma, peritoneal fluid, and amniotic fluid) gave discrepant IGFBP-3 values between RIA and Western ligand blot.(ABSTRACT TRUNCATED AT 400 WORDS)     

Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men

OBJECTIVE: To determine the concentrations of nevirapine (NVP), lamivudine (3TC) and stavudine (D4T) in seminal and blood plasma in HIV-1-infected men. METHODS: Twelve HIV-1-infected men on NVP-containing regimens including 3TC (n = 8) or D4T (n = 11) provided 23 blood plasma and 22 seminal plasma samples for drug concentration and viral load quantitation. Concentrations of all drugs were assessed by sensitive validated high performance liquid chromatography (HPLC) assays. Blood plasma and seminal plasma viral loads were measured using nucleic acid sequence-based amplification (NASBA). Samples were grouped according to time after drug ingestion, 0-2, 2-4, 4-8 and 8-12 h. For matched seminal and blood plasma samples, obtained within 1 h of each other, a seminal:blood plasma ratio was calculated. RESULTS: The concentration of NVP in seminal plasma appeared to mirror the concentrations in blood plasma. Absolute median seminal plasma NVP concentrations at 0-2, 2-4, 4-8 and 8-12 h were 3.1 microg/ml (range 1.7-4.89), 2.68 microg/ml (2.5-3.9), 2.5 microg/ml (2.3-2.7) and 3.09 microg/ml (1.3-9.1). The median seminal:blood plasma ratios for the four time periods were 0.54 (range 0.34-0.85), 0.83 (range 0.43-1.08), 0.53 (0.48-0.59), and 0.61 (0.59-0.78). 3TC and D4T appeared to reach concentrations in seminal plasma of a similar magnitude or higher than concentrations in blood plasma. The median seminal plasma viral load for all patients was less than 800 copies/ml (range < 800-11000). The median blood plasma viral load was less than 400 copies/ml (< 400-1100). CONCLUSION: NVP reaches concentrations in the semen approximately 60% of those in the blood plasma throughout the 12 h dosing period. In a smaller dataset, 3TC and D4T concentrations in blood plasma and seminal plasma were similar. These data may well have implications for the evolution of drug-resistant virus within the genital tract.     

A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk

OBJECTIVE: To evaluate the safety, tolerability, and trough levels of three pre-exposure prophylaxis regimens of nevirapine among HIV-1-uninfected subjects at high risk for HIV-1 infection. METHODS: A phase I/II trial (HIVHOP 101) in which 33 such uninfected subjects received a 200 mg tablet of nevirapine once weekly (cohort A, n = 12), twice weekly (cohort B, n = 12), or every other day (cohort C, n = 9) for 12 weeks. Clinical signs/symptoms, laboratory parameters, and nevirapine trough levels were assessed at entry and at 1, 2, 4, 6, 9, and 12 weeks, with a follow-up sample at 16 weeks. RESULTS: No subject experienced clinical symptoms attributed to nevirapine, including rash. There were no significant changes in liver enzyme levels from baseline to week 12 in the three cohorts, except for glutamyl transpeptidase in cohort B. Median nevirapine trough levels at weeks 1 and 12 were 119 ng/ml (range, < 25-205) and 135 ng/ml (range, < 25-1065), respectively, for cohort A, 569 ng/ml (range, 135-2641) and 431 ng/ml (range, 42-2454) for cohort B, and 1942 ng/ml (range, 1214-2482) and 943 ng/ml (range, 262-5281) for cohort C. No subject became HIV-1 antibody positive by week 16. CONCLUSIONS: A single dose of nevirapine taken once weekly, twice weekly, or every other day for 12 weeks was safely tolerated by the subjects in this small study, and resulted in nevirapine levels well above the IC (inhibitory concentration of 50%: 10 ng/ml) over the 12-week period in nearly all evaluable subjects. (50)     

Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda

OBJECTIVES: Polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. Although nevirapine is used extensively in Africa, the influence of CYP2B6 genotype on nevirapine exposure has not been assessed in this population. We aimed to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Additional polymorphisms in the CYP and multidrug resistance protein-1 (MDR-1) genes were also assessed for their impact on nevirapine concentrations. METHODS: The following genotypes were determined in all subjects using polymerase chain reaction-restriction fragment length polymorphism: CYP2B6 G516T, MDR-1 C3435T and G2677T, CYP3A4(*)1B and CYP3A5(*)3. Nevirapine plasma concentrations were determined using high-performance liquid chromatography in 23 HIV-infected patients who were generally healthy and had been taking nevirapine 200 mg twice daily for at least 14 days. Analysis of variance with post hoc testing was used to compare nevirapine concentrations among CYP2B6 genotype groups. RESULTS: The median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs 4181 and 5559 ng/mL for GG and GT individuals, respectively (GG vs TT median ratio=1.82; P=0.011). The mean ratio for TT vs GG individuals (95% confidence interval) was 1.51 (1.18, 1.84). No associations were observed between the other polymorphisms studied and nevirapine concentrations. CONCLUSIONS: CYP2B6 G516T significantly influenced nevirapine trough concentrations in HIV-infected patients in Uganda. Additional studies in larger patient populations are necessary to further define the potential clinical impact of these preliminary findings.     

Absence of association between MDR1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy

OBJECTIVE: The relationship between MDR1 single nucleotide polymorphisms (SNP) and the pharmacokinetic or pharmacodynamic responses to protease inhibitors has been recently challenged. AIM: The objective of the present study was to determine whether MDR1 genetic polymorphisms in exons 21 and 26 (G2677T/A and C3435T) are in association with indinavir (IDV) plasma concentrations and/or therapeutic response to highly active antiretroviral therapy (HAART) in HIV-infected patients treated with unboosted IDV containing regimens. METHODS: MDR1 genotyping was performed in a population of 139 HIV-1-positive patients followed during 72 weeks, as part of the previous study called ANRS 081 'Trianon'. The primary study was a randomized trial comparing over 72 weeks the efficacy of two antiretroviral drug combinations in a population of adult HIV-1-infected patients: group 1, [lamivudine (3TC) - stavudine (d4T) - IDV (800 mg three times daily)] and group 2, [Nevirapine (NVP) - d4T - IDV (1000 mg three times daily)]. RESULTS: MDR1 SNPs analyzed separately or combined into haplotypes did not show any significant association with IDV pharmacokinetics nor response to HAART. Mean modelled IDV peak and trough concentrations, as well as clearance modelled from pharmacokinetic model, after 8 weeks of therapy were not significantly different between patients carrying the wild-type haplotype GG-CC (at position 2677 and 3435 respectively) and others. CONCLUSIONS: Our results do not support an association between MDR1 genetic polymorphisms and modelled IDV clearance or clinical response to HAART.     

HIV in body fluids during primary HIV infection: implications for pathogenesis, treatment and public health

OBJECTIVE: To describe initial viral dissemination to peripheral tissues and infectious body fluids during human primary HIV infection. DESIGN: Observational cohort study. METHODS: Blood plasma, cerebrospinal fluid (CSF), seminal plasma, cervicovaginal lavage fluid and/or saliva were sampled from 17 individuals with primary HIV infection (range of time from symptoms onset to sampling, 8--70 days) and one individual with early infection (168 days). Subjects' HIV-1 RNA levels in each fluid were compared with levels from antiretroviral-naive controls with established HIV infection. For study subjects, correlations were assessed between HIV-1 RNA levels and time from symptoms onset. Responses to antiretroviral therapy with didanosine + stavudine + nevirapine +/- hydroxyurea were assessed in each compartment. RESULTS: HIV-1 RNA levels were highest closest to symptoms onset in blood plasma (18 patients) and saliva (11 patients). CSF HIV-1 RNA levels (five patients) appeared lower closer to symptoms onset, although they were higher overall in primary versus established infection. Shedding into seminal plasma (eight patients) and cervicovaginal fluid (two patients) was established at levels observed in chronic infection within 3--5 weeks of symptoms onset. High-level seminal plasma shedding was associated with coinfection with other sexually transmitted pathogens. Virus replication was suppressed in all compartments by antiretroviral therapy. CONCLUSIONS: Peak level HIV replication is established in blood, oropharyngeal tissues and genital tract, but potentially not in CSF, by the time patients are commonly diagnosed with primary HIV infection. Antiretroviral therapy is unlikely to limit initial virus spread to most tissue compartments, but may control genital tract shedding and central nervous system expansion in primary infection.     

Determination of indinavir and nelfinavir trough plasma concentration efficacy thresholds according to virological response in HIV-infected patients

BACKGROUND: There is evidence to suggest a pharmacokinetic-pharmacodynamic relationship in HIV-infected patients receiving protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART); however, the effective trough PI plasma concentrations achieved have not been precisely determined. METHODS: The relationship between HIV viral load and concomitant PI trough plasma concentration (C(trough)) was evaluated in 101 patients receiving at least 4 months of thrice daily indinavir (IDV)-containing (n=68) or nelfinavir (NFV)-containing (n=33) HAART. The more discriminating C(trough) efficacy thresholds were determined statistically for each PI by using the raw C(trough) and the time-corrected C(trough), using the precise delay since the last PI intake and the half-life of each PI. RESULTS: For IDV (P=0.002) and NFV (P=0.019) median C(trough) levels were higher in patients with undetectable viral load [0.23 mg/L (n=30) and 2.3 mg/L (n=16) respectively] than in patients with detectable viral load [0.11 mg/L (n=38) and 0.6 mg/L (n=17) respectively]. C(trough) levels of IDV (r=-0.45; P<0.0001) and NFV (r=-0.43; P=0.011) were correlated with the concomitant viral load. The more discriminating C(trough) efficacy thresholds were estimated statistically as 0.12 mg/L for IDV and 0.5 mg/L for NFV. When C(trough) values were time-corrected, the C(trough) efficacy thresholds, 8 h after the last intake, were 0.15 mg/L for IDV and 0.65 mg/L for NFV. CONCLUSIONS: These results support the importance of achieving minimal effective C(trough) to improve the virological efficacy of PI-containing HAART, and specify the target concentrations for IDV and NFV.     

Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients

OBJECTIVES: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. METHODS: Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach. RESULTS: Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017. CONCLUSIONS: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.     

Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study

OBJECTIVE: To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. DESIGN: Open-label, multi-dose, pharmacokinetic pilot study. PATIENTS: Seven HIV-1-infected individuals who were treated with saquinavir hard gelatin capsules 400 mg twice daily + ritonavir liquid formulation 400 mg twice daily were switched to saquinavir soft gelatin formulation 1600 mg once daily in combination with ritonavir liquid formulation 200 mg once daily (day 0). Patients were instructed to ingest saquinavir and ritonavir simultaneously in the morning and with a meal. METHODS: Steady-state pharmacokinetics of saquinavir and ritonavir were assessed during a 24 h dosing interval after 2 weeks of continued therapy (day 14). Plasma saquinavir and ritonavir concentrations were measured using a validated high performance liquid chromatography assay. In addition, plasma HIV-1 RNA, and fasting total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were measured on days 0 and 14. A non-compartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC[0-24h]), the maximum and trough plasma concentrations (Cmax and Cmin), the time to reach Cmax (Tmax), the elimination half-life (t1/2), the apparent clearance (Cl/F), and the apparent volume of distribution (V/F). RESULTS: Median (range) values of the pharmacokinetic parameters for saquinavir after 2 weeks of treatment were: AUC[0-24h], 19,802h* ng/ml (3720-74,016); Cmax, 2936 ng/ml (573-6848); Cmin, 84 ng/ml (11-854); Tmax, 3.5 h (3.0-4.0), t1/2, 6.8 h (4.6-10.2); Cl/F, 81 l/h (22-430); V/F, 1189 l (215-3086). Ritonavir concentrations were always below the 90% effective concentration of 2100 ng/ml (median Cmax, 1323 ng/ml; range, 692-1528 ng/ml). No significant changes were observed for total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels between days 0 and 14 (P > or = 0.24). In six out of seven patients the fasting serum triglyceride levels were lower 2 weeks after the treatment switch (median decrease was 32%, P = 0.03). No significant changes in plasma HIV-1 RNA concentrations were observed between days 0 and 14. The regimen was generally well tolerated. CONCLUSIONS: This pharmacokinetic study indicates that the combination of 1600 mg of saquinavir (soft gelatin capsules) and 200 mg of ritonavir (liquid formulation) in a once-daily dosing regimen generally results in therapeutic plasma concentrations of saquinavir. Due to the large interindividual variation in saquinavir exposure, the monitoring of saquinavir concentrations in plasma is warranted. These pharmacokinetic findings rationalize the further clinical evaluation of once-daily dosing of this combination of protease inhibitors.     

Principles and practice of HIV-protease inhibitor pharmacoenhancement

Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate. A significant number of patients receiving PIs two or three times daily will have trough (C_trough or C_min) plasma concentrations, which are close to, or below, the plasma protein binding‐corrected inhibitory concentration (IC₅₀ or IC₉₅) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval. Beneficial drug–drug interactions have been shown to improve PI pharmacokinetics. Ritonavir (RTV) inhibits the key enzymes that limit the bioavailability or speed the metabolism of other PIs. It is therefore increasingly used for boosting and maintaining PI plasma concentrations. At low (100 mg twice a day) doses it acts as a pharmacoenhancer of indinavir (IDV), amprenavir, saquinavir, lopinavir and to a more limited degree nelfinavir. Using a pharmacoenhancer with a PI results in increased exposure to the PI, higher C_min levels, and in most cases prolonged elimination half‐lives. The long‐term clinical benefits of PK enhancing are unknown as are the long‐term toxicities, although the incidence of nephrolithiasis with IDV appears increased when IDV is combined with low‐dose RTV in HIV‐infected patients. Head‐to‐head clinical comparisons of boosted PI regimens will help answer some of the questions that remain with regard to PK enhancement.     

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.     

Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment

BACKGROUND: The magnitude of infant antiretroviral (ARV) exposure from breast milk is unknown. METHODS: We measured concentrations of nevirapine, lamivudine, and zidovudine in serum and whole breast milk from human immunodeficiency virus type 1 (HIV-1)-infected women in Botswana receiving ARV treatment and serum from their uninfected, breast-feeding infants. RESULTS: Twenty mother-infant pairs were enrolled. Maternal serum concentrations of nevirapine were high (median, 9534 ng/mL at a median of 4 h after nevirapine ingestion). Median breast-milk concentrations of nevirapine, lamivudine, and zidovudine were 0.67, 3.34, and 3.21 times, respectively, those in maternal serum. The median infant serum concentration of nevirapine was 971 ng/mL, at least 40 times the 50% inhibitory concentration and similar to peak concentrations after a single 2-mg/kg dose of nevirapine. The median infant serum concentration of lamivudine was 28 ng/mL, and the median infant serum concentration of zidovudine was 123 ng/mL, but infants were also receiving zidovudine prophylaxis. CONCLUSIONS: HIV-1 inhibitory concentrations of nevirapine are achieved in breast-feeding infants of mothers receiving these ARVs, exposing infants to the potential for beneficial and adverse effects of nevirapine ingestion. Further study is needed to understand the impact of maternal ARV treatment on breast-feeding HIV-1 transmission, infant toxicity, and HIV-1 resistance mutations among infected infants.     

The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.

OBJECTIVE: To explore the steady-state plasma pharmacokinetics of indinavir in twice daily dosing regimens with and without the co-administration of 100 mg ritonavir. DESIGN: Observational pharmacokinetic study. PATIENTS: HIV-1-infected individuals who use indinavir alone (1200 mg twice daily, n = 6), or the combination of 100 mg ritonavir twice daily plus either 800 mg (n = 6), or 1200 mg indinavir twice daily (n = 2). METHODS: Steady-state pharmacokinetics of indinavir and ritonavir were assessed by drawing 12 blood samples during an 8-h period after ingestion of the medication. RESULTS: Significant differences were observed for indinavir pharmacokinetics between the dosing regimens indinavir 1200 mg twice daily alone and indinavir/ ritonavir 800/100 mg twice daily with respect to the mean trough concentration (0.21 and 0.99 microg/ml, respectively, P = 0.002), the mean maximum concentration (13.79 and 8.74 microg/ml, respectively, P = 0.028), and for the mean plasma elimination half-life (1.6 and 3.2 h, respectively, P = 0.001). The combination indinavir/ritonavir 1200/100 mg twice daily led to very high exposure to indinavir and was not well tolerated. However, the combination indinavir/ritonavir 800/100 mg twice daily was well tolerated and resulted in therapeutic concentrations of indinavir with improved trough concentrations and similar maximum concentrations as observed with the licensed dosage of 800 mg three times daily. CONCLUSION: Combination of indinavir and 100 mg ritonavir in twice daily dosing regimens significantly affects the pharmacokinetic profile of indinavir. The results of this observational study provide a pharmacologic basis for the combination of indinavir (800 mg) and ritonavir (100 mg) in twice daily dosing regimens.     

Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy.

OBJECTIVE: The primary objective of this study was to assess the kinetics of ketoprofen in synovial fluid and intra-articular tissues in relation to plasma. The secondary objective was to study whether intra-articular tissues act as reservoirs. METHODS: The ketoprofen concentration was analysed in plasma, synovial fluid and intra-articular tissues after single application of a 30 mg plaster (n = 40), multiple applications for 5 days (n = 30) or oral intake of 50 mg (n = 30) in patients undergoing knee arthroscopy. RESULTS: Median CMax values after topical application were 12.8 ng/ml in synovial fluid, 56.7 ng/g in synovial tissue, 349.3 ng/g in meniscus and 568.9 ng/g in cartilage. CONCLUSION: Topical applications of ketoprofen allow the attainment of high intra-articular tissue concentrations.