No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC_0–12) and concentration prior to dosing (C_predose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC_0–12 or C_predose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.     

Pharmacokinetics of Fosamprenavir plus Ritonavir in Human Immunodeficiency Virus Type 1-Infected Adult Subjects with Hepatic Impairment

The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (C_max), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC_(0-τ)], similar values for the concentration at the end of the dosing interval (C_τ), and 114% higher unbound C_τ values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir C_max values, 27% lower AUC_(0-24) values, 57% lower C_τ values, and 21% higher unbound amprenavir C_τ values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir C_max values, 23% lower AUC_(0-24) values, 38% lower C_τ values, and similar unbound amprenavir C_τ values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC_(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.Among the estimated 40 million persons infected with human immunodeficiency virus (HIV) worldwide, an estimated 2 to 4 million are chronically infected with hepatitis B virus (HBV) and an estimated 4 to 5 million are chronically infected with hepatitis C virus (HCV) (1). The prevalence of HBV and HCV coinfection in HIV-infected subjects is correlated with intravenous drug use as an HIV risk factor; the prevalence is above 40% in some southern European countries (2, 5, 7). Those with hepatitis infection often have some degree of liver impairment. For those with chronic HCV infection alone, the estimated rate of progression to cirrhosis is 2 to 20% over 20 years (1).Dosing recommendations for the hepatically impaired are available for several protease inhibitors, although most exclude those with severe impairment and/or include safety precautions. Until recently, unboosted amprenavir was the only protease inhibitor indicated for use in the treatment of HIV-infected patients with severe hepatic impairment; indeed, all antiretroviral agents other than selected nucleosides are contraindicated for this difficult-to-treat population. Thus, more options are clearly needed.Fosamprenavir is the prodrug of the HIV type 1 (HIV-1) protease inhibitor amprenavir and is often used in combination with low-dosage ritonavir to increase plasma amprenavir concentrations by inhibiting amprenavir CYP3A4-mediated metabolism. We studied fosamprenavir/ritonavir combinations administered to HIV-infected subjects with mild, moderate, and severe hepatic impairment as well as to control subjects with normal hepatic function for 2 weeks. Because amprenavir is highly bound to plasma proteins (including albumin and α₁-acid glycoprotein [AAG]) that are synthesized in the liver, plasma unbound amprenavir concentrations and percent unbound were evaluated in the present study. The primary goals of this study were to evaluate the impact of hepatic impairment on amprenavir and ritonavir pharmacokinetics (PK) and to determine dosing recommendations for this patient population.     

Phase I Safety,Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir,Efavirenz, or Rifampin

There is an urgent need for new antituberculosis (anti-TB) drugs, including agents that are safe and effective with concomitant antiretrovirals (ARV) and first-line TB drugs. PA-824 is a novel antituberculosis nitroimidazole in late-phase clinical development. Cytochrome P450 (CYP) 3A, which can be induced or inhibited by ARV and antituberculosis drugs, is a minor (∼20%) metabolic pathway for PA-824. In a phase I clinical trial, we characterized interactions between PA-824 and efavirenz (arm 1), lopinavir/ritonavir (arm 2), and rifampin (arm 3) in healthy, HIV-uninfected volunteers without TB disease. Participants in arms 1 and 2 were randomized to receive drugs via sequence 1 (PA-824 alone, washout, ARV, and ARV plus PA-824) or sequence 2 (ARV, ARV with PA-824, washout, and PA-824 alone). In arm 3, participants received PA-824 and then rifampin and then both. Pharmacokinetic sampling occurred at the end of each dosing period. Fifty-two individuals participated. Compared to PA-824 alone, plasma PA-824 values (based on geometric mean ratios) for maximum concentration (C_max), area under the concentration-time curve from 0 to 24 h (AUC_0–24), and trough concentration (C_min) were reduced 28%, 35%, and 46% with efavirenz, 13%, 17%, and 21% with lopinavir-ritonavir (lopinavir/r) and 53%, 66%, and 85% with rifampin, respectively. Medications were well tolerated. In conclusion, lopinavir/r had minimal effect on PA-824 exposures, supporting PA-824 use with lopinavir/r without dose adjustment. PA-824 exposures, though, were reduced more than expected when given with efavirenz or rifampin. The clinical implications of these reductions will depend upon data from current clinical trials defining PA-824 concentration-effect relationships. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01571414","term_id":"NCT01571414"}}NCT01571414.)     

Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C_{12 h}) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC_0-∞) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C_max) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C_{12 h} GMR (90% CI) was 0.79 (0.49, 1.28); AUC_0-∞ was 0.64 (0.52, 0.80); and C_max was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.     

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C_min and C_max, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C_min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C_mins below 1 mg/liter. A significantly higher percentage of children with C_mins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log₁₀ copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C_mins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily has improved compliance for adults and shown good antiretroviral efficacy (12); moreover, the treatment could be better tolerated in the long term (5, 6, 13). For children, the efficacy and tolerance of this ddI-3TC-EFV combination have not been investigated. The aims of the BURKINAM (ANRS 12103) study, then, were to investigate the pharmacokinetics of EFV, ddI, and 3TC given once daily in children 30 months to 15 years old and to evaluate the efficacy and tolerance of this combination.EFV is metabolized exclusively via CYP2B6 (cytochrome P450 isoenzyme) in the liver (20). Several factors (covariates), such as age (9), duration of treatment (7), or ethnicity (8), may affect EFV metabolism. In the present work, a population pharmacokinetic study was performed with African children in order to describe the concentration-time courses of EFV and to study the influence of covariates on EFV pharmacokinetics.Relationships between EFV antiretroviral efficacy/toxicity and plasma EFV concentrations have been established previously for adults (14). No or weak pharmacokinetic-pharmacodynamic relationships were reported in children. Moreover, pediatric studies suggested that the actual recommended EFV dosage produced insufficient concentrations of the drug in plasma (19, 21). In this study, the correlation between concentrations and efficacy was finally tested, the threshold area under the concentration-time curve (AUC) and minimum concentration of the drug in plasma (C_min) that improved efficacy were determined, and an optimized dosing scheme was simulated.     

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady‐state exposures (area under the concentration curve from 0 to 12‐h [AUC_0–>12 h]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m²/dose) or a pharmacokinetically guided dose targeting an AUC_0–>12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in‐target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Sorafenib pharmacokinetics (PKs) show large interindividual variability given fixed doses (90 mg/m²/dose twice daily). This leads to a wide exposure range, particularly higher exposures, which can lead to hand foot skin reaction (HFSR), withheld doses, and therefore a possible lower antitumor efficacy.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can PK and pharmacodynamic modeling and simulation approaches provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study provides evidence, through PK and pharmacodynamic simulations, that it is possible to decrease the variability of sorafenib exposure, increase the percentages of studies in a target range, and reduce the occurrence of HFSR.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials, including our prospective protocol in children with rare solid malignancies.     

Interactions between amprenavir and the lopinavir-ritonavir combination in heavily pretreated patients infected with human immunodeficiency virus

OBJECTIVE: This pharmacokinetic study was designed to characterize interactions between amprenavir and the lopinavir-ritonavir combination in patients infected with human immunodeficiency virus in whom previous antiretroviral therapy had failed. METHODS: Twenty-seven patients included in a randomized clinical trial (ANRS [National Agency for AIDS Research] Protocol 104) participated in this study. They were randomized to receive ritonavir at a dose of either 100 mg twice daily or 200 mg twice daily. For the first 2 weeks of therapy, they were randomly assigned to receive lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily), amprenavir (600 mg twice daily) plus ritonavir (100 mg twice daily), lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily) plus additional ritonavir (100 mg twice daily), or amprenavir (600 mg twice daily) plus ritonavir (200 mg twice daily). From week 3 onward, all patients received amprenavir plus lopinavir-ritonavir with or without an additional ritonavir dose (100 mg twice daily). The pharmacokinetics of the 3 drugs was studied in weeks 2 and 6 of therapy. RESULTS: Median amprenavir concentrations decreased by 54% (P =.004) when lopinavir was added to the amprenavir-ritonavir regimen. Lopinavir weakly displaced amprenavir from plasma proteins: The average unbound fraction of amprenavir was 0.089 in week 2 and 0.114 in week 6 (P =.03), but this did not fully account for the observed interaction. Increasing the ritonavir dose did not affect the amprenavir concentration. The relationship between lopinavir and ritonavir concentrations fitted a maximum effect (E(max)) model;the average concentration of ritonavir that yielded a lopinavir concentration of 8119 ng/mL (50% of E(max)) was 602 ng/mL (coefficient of variation, 22%). There was a significant relationship between the lopinavir inhibitory quotient and the virologic response in week 2 (P =.005). CONCLUSION: Lopinavir markedly decreases the amprenavir concentration during amprenavir and lopinavir-ritonavir combination therapy. The inhibitory quotients were more predictive of the short-term virologic response than was the level of drug exposure.     

Minimal Removal of Raltegravir by Hemodialysis in HIV-Infected Patients with End-Stage Renal Disease

Little is known about raltegravir removal by hemodialysis in patients with end-stage renal disease (ESRD). We therefore measured raltegravir concentrations in plasma in pre- and postdialyzer blood samples from 2 ESRD HIV-infected patients. The hemodialysis extraction ratio and raltegravir hemodialysis clearance were 5.5% and 9.1 ml/min in patient 1 and 9.5% and 19.1 ml/min in patient 2, respectively. Our results suggest minimal raltegravir removal by hemodialysis with no specific raltegravir dosage adjustments required in HIV-infected patients undergoing hemodialysis.The prevalence of chronic renal disease in HIV-infected patients has been estimated to be 5% to 40% (1, 6), depending on the definition applied in each study, and on the racial composition and comorbidity of the population studied. In any case, the progressive aging of the HIV-infected population together with the presence of some comorbid diseases (such as diabetes or hypertension), as well as direct toxicity derived from the antiretroviral drugs, provides a basis for growing concern that the prevalence of chronic renal disease and end-stage renal disease (ESRD) may increase in the future (8). This means that an increasing number of HIV-infected patients will need renal replacement therapy.Raltegravir is an integrase inhibitor of HIV with demonstrated efficacy in naïve and treatment-experienced HIV-infected patients (5, 9). It is mainly metabolized by glucuronidation through UGT1A1 in the liver, with only 9% of the raltegravir dose excreted unchanged in the urine. Raltegravir is approximately 83% bound to plasma proteins, has a low molecular weight, and presents a relatively high solubility in water (blood-to-plasma partition coefficient, 0.6) (4). These characteristics make it possible for hemodialysis to remove raltegravir from plasma in patients with ESRD. As a result, subtherapeutic concentrations of raltegravir after the dialysis sessions might be possible.Here we report two cases of ESRD HIV-infected patients undergoing routine hemodialysis who were receiving antiretroviral therapy with raltegravir. To evaluate the effect of hemodialysis on raltegravir clearance, predialyzer and postdialyzer blood samples were collected at the beginning and end of a single dialysis session. Both patients gave their oral informed consent before sampling.Blood samples for raltegravir determinations were collected into potassium and EDTA-containing 10-ml tubes. Plasma was isolated by centrifugation (3,200 × g for 15 min) and stored at −20°C until analysis. Raltegravir concentrations in plasma were determined by high-performance liquid chromatography with a fluorescence detector (HPLC multifluorescence detector 2475; Waters) according to a validated method (7). Chromatographic separation was performed on a Sunfire C₁₈ column (5 μm; 4.6 by 150 mm) (Waters). The mobile phase was phosphate buffer-acetonitrile (25 mM, pH 3). The fluorescence detector was set at 299 and 396 nm for excitation and emission wavelengths, respectively. The drug was extracted from plasma by liquid-liquid extraction with tert-butyl methyl ether. The method was linear over the range of 10 to 5,000 ng/ml, with quality controls at 840 ng/ml, 360 ng/ml, and 60 ng/ml. At least 98% of raltegravir was recovered at the three levels of concentration assessed. The intra- and interday coefficients of variation were less than 10%.The hemodialysis extraction ratio (ER) for raltegravir was calculated at the beginning of the dialysis session as ER = (C_in − C_out)/C_in (2), where C_in is predialyzer raltegravir concentration in plasma (i.e., blood entering the kidney machine) and C_out is postdialyzer raltegravir concentration in plasma (i.e., blood leaving the kidney machine).Raltegravir dialysis clearance (CL_D) in terms of plasma was calculated as CL_D = ER × Q_p (2), where Q_p is plasma flow through the dialyzer.Because raltegravir is minimally distributed into red blood cells (4), correction for hematocrit was made according to the equation Q_p = Q_b(1 − H) (2), where Q_b is the blood flow through the dialyzer and H is the patient''s hematocrit.Patient 1 was a 53-year-old man who was diagnosed with HIV infection in 1984. The patient had received multiple antiretroviral regimens and at the time of the study had been receiving therapy with nevirapine (200 mg twice daily) and raltegravir (400 mg twice daily) for the previous 6 months. HIV-1 RNA load in plasma was <50 copies/ml, and CD4⁺ T-cell count was 863 cells/mm³. His most relevant underlying diseases included hepatitis C virus (HCV) coinfection, hypertension, hyperlipidemia, and severe ischemic heart disease. The patient had ESRD and had been undergoing hemodialysis three times a week (Fresenius F8HPS) for the previous 2 years. Each hemodialysis session lasted approximately 4 h. On hemodialysis days, the patient delayed the morning raltegravir dose until the end of the dialysis session. Dialysate and blood flows were held constant at 500 ml/min and 300 ml/min, respectively.Patient 2 was a 50-year-old man who was diagnosed with HIV infection in 1992. He had been receiving antiretroviral therapy with efavirenz (600 mg once daily) plus tipranavir-ritonavir (500/200 mg twice daily, respectively) and raltegravir (400 mg twice daily). HIV-1 RNA load in plasma was <50 copies/ml, and CD4⁺ T-cell count was 976 cells/mm³. He had been diagnosed with hypertension. The patient had been undergoing 4-hour hemodialysis sessions three times a week (Polyflux 17C). Dialysate and blood flows were 500 ml/min and 300 ml/min, respectively.Table ​Table11 summarizes raltegravir concentrations in plasma in pre- and postdialyzer samples at the beginning and end of the dialysis session. At the end of the session, raltegravir concentrations had decreased by 68% in patient 1 and by 45% in patient 2. However, the hemodialysis extraction ratio and raltegravir hemodialysis clearance were only 5.5% and 9.1 ml/min in patient 1 and 9.5% and 19.1 ml/min in patient 2, respectively. Both patients maintained raltegravir concentrations in plasma higher than the protein-binding-adjusted 95% inhibitory concentration of 15 ng/ml at the end of the dialysis session (M. Miller, M. Witmer, K. Stilmock, P. Felock, L. Ecto, J. Flynn, W. Schleif, G. Dornadula, R. Danovich, and D. Hazuda, presented at the 16th International AIDS Conference, 2006).

TABLE 1.

Raltegravir concentrations in plasma in pre- and postdialyzer samples during the hemodialysis session^a

Pharmacokinetics of Darunavir/Ritonavir and Rifabutin Coadministered in HIV-Negative Healthy Volunteers

The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC_12h) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (C_min) increased by 64% and the maximum plasma concentration (C_max) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUC_τ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.The protease inhibitor (PI) darunavir (DRV) with low-dose ritonavir (DRV/r) has demonstrated substantial efficacy and safety across the whole treatment spectrum of HIV-1-infected patients (6, 13, 14). DRV/r is approved in the United States (25), Europe (26), and other countries for treatment-experienced (600/100 mg twice a day [BID]) and treatment-naïve (800/100 mg once a day [QD]) HIV-1-infected adult patients.Rifabutin (RFB) is an antibiotic used in patients with HIV infection to prevent and treat disseminated Mycobacterium avium complex infections and (in combination with other agents) to treat tuberculosis (16). Patients already receiving DRV/r may, therefore, also need to receive RFB.The predominant metabolite of RFB is 25-O-desacetylrifabutin (desRFB), which is normally present at 10-fold lower plasma concentrations than RFB. DesRFB has similar activity to RFB and contributes up to 10% of the antimicrobial activity (16). DRV, ritonavir, and RFB are metabolized predominantly by the isoenzyme cytochrome P450 3A4 (CYP3A4) (16, 25, 26). Ritonavir and DRV are inhibitors of CYP3A4 metabolism (25, 26), and RFB is reported to be an inducer of CYP3A4 (16). A pharmacokinetic (PK) drug-drug interaction is therefore expected when DRV/r and RFB are coadministered.This study examines the PK interaction between DRV/r and RFB in HIV-negative healthy volunteers and provides dose recommendations for coadministration in HIV-1-infected patients.     

Clinical Pharmacodynamics of Cefepime in Patients Infected with Pseudomonas aeruginosa

We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [fT > MIC], the ratio of the minimum concentration of free drug to the MIC [fC_min/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 μg/ml, resulting in median fT > MIC, fC_min/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an fT > MIC of ≤60% (77.8% failed cefepime therapy when fT > MIC was ≤60%, whereas 36.2% failed cefepime therapy when fT > MIC was >60%; P = 0.013). A similar fT > MIC target of ≤63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with fT > MIC values of ≤60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% fT > MIC will minimize the possibility of a poor microbiological response.Cefepime is a commonly used broad-spectrum cephalosporin with potent activity against a wide variety of Gram-negative bacteria, including Pseudomonas aeruginosa (11). Despite its extensive use, its presence in multiple clinical guidelines, and numerous indications for its use (1, 16, 20, 26), a recent meta-analysis found treatment with cefepime to be associated with an increase in the patient mortality rate compared to that obtained by the use of other antimicrobial agents. Importantly, in that study the pharmacokinetics and pharmacodynamics (i.e., cefepime exposure and MIC of the infecting organisms) of cefepime were not included, leaving out a critical part of understanding antibiotic treatment outcomes (25).The pharmacodynamic relationship historically thought to be predictive of cefepime efficacy, as with all beta-lactams, is the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism (fT > MIC) (24). Numerous in vivo animal studies with various cephalosporins have suggested that an fT > MIC target of 50 to 70% is required to achieve maximal reductions in the numbers of CFU of Gram-negative bacteria (5). However, the data available from evaluations of the clinical pharmacodynamics of cephalosporin have been less decisive and are discordant with the findings of in vivo animal studies. Two recently published reports of studies examining the pharmacodynamics of cefepime in patients with infections caused by various Gram-negative bacteria found the ratio of the minimum cefepime concentration to the MIC (C_min/MIC) to be the parameter best associated with a microbiological response, while another study defined the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC) to be the most predictive (13, 17, 23). Moreover, when the T > MIC for total drug was evaluated, those investigators found that targets of 90 to 100% were required for predictable microbiological success (13, 23). Given these discrepancies, coupled with the fact that cefepime is primarily used for the treatment of P. aeruginosa infections, we sought to focus on a pharmacodynamic analysis of patients with severe infections caused by this organism.     

Dosing Regimens of Cotrimoxazole (Trimethoprim-Sulfamethoxazole) for Melioidosis

Melioidosis is an infectious disease with a propensity for relapse, despite prolonged antibiotic eradication therapy for 12 to 20 weeks. A pharmacokinetic (PK) simulation study was performed to determine the optimal dosing of cotrimoxazole (trimethoprim-sulfamethoxazole [TMP-SMX]) used in current eradication regimens in Thailand and Australia. Data for bioavailability, protein binding, and coefficients of absorption and elimination were taken from published literature. Apparent volumes of distribution were correlated with body mass and were estimated separately for Thai and Australian populations. In vitro experiments demonstrated concentration-dependent killing. In Australia, the currently used eradication regimen (320 [TMP]/1,600 [SMX] mg every 12 h [q12h]) was predicted to achieve the PK-pharmacodynamic (PD) target (an area under the concentration-time curve from 0 to 24 h/MIC ratio of >25 for both TMP and SMX) for strains with the MIC₉₀ of Australian strains (≤1/19 mg/liter). In Thailand, the former regimen of 160/800 mg q12h would not be expected to attain the target for strains with an MIC of ≥1/19 mg/liter, but the recently implemented weight-based regimen (<40 kg [body weight], 160/800 mg q12h; 40 to 60 kg, 240/1,200 mg q12h; >60 kg, 320/1,600 mg q12h) would be expected to achieve adequate concentrations for strains with an MIC of ≤1/19 mg/liter. The results were sensitive to the variance of the PK parameters. Prospective PK-PD studies of Asian populations are needed to optimize TMP-SMX dosing in melioidosis.Melioidosis, a serious human infectious disease caused by the gram-negative bacterium Burkholderia pseudomallei, is endemic in northern Australia and southeast Asia. The in-hospital mortality rate averages 20% in Australia and 40 to 50% in northeast Thailand. In survivors of acute disease, recurrence after apparent clinical response, despite appropriate antibiotic treatment, is reported at rates of between 13 and 23% (5, 9). Molecular typing has determined that the majority (75%) of recurrent disease is due to persistence and subsequent relapse of the original infecting strain, with 25% of cases being second infections (17). Current antibiotic recommendations are for an intensive intravenous phase (ceftazidime or a carbapenem) for 10 to 14 days followed by a prolonged eradication phase (trimethoprim-sulfamethoxazole [TMP-SMX], or cotrimoxazole, alone or in combination with doxycycline) (6).Dosing regimens for the eradication phase of treatment vary between countries. In Australia, a TMP-SMX dose of 320/1,600 mg (two double-strength tablets) every 12 h (q12h) is recommended. In Ubon Ratchathani, Thailand, a TMP-SMX dose of 160/800 mg (two single-strength tablets) q12h (with doxycycline) has been used previously. However, a new weight-based dosing protocol (for patients of <40 kg [body weight], 160/800 mg q12h; 40 to 60 kg, 240/1,200 mg q12h; and >60 kg, 320/1,600 mg q12h, plus doxycycline) is now used.TMP-SMX is a commonly used synergistic antibiotic combination that acts on successive enzymes in the bacterial folate synthesis pathway. The appropriate pharmacokinetic-pharmacodynamic (PK-PD) parameter has not been defined for TMP-SMX. Limited data from children with pneumococcal otitis media suggested that clinical efficacy correlates with the proportion of time when antibiotic concentrations exceed the MIC of the infecting organism (8).In this study, we performed time-kill studies to assess the likely PK-PD target and evaluated the TMP-SMX dosing regimens using a simulation model with Thai and Australian populations.     

Drug-Drug Interaction Study of Ketoconazole and Ritonavir-Boosted Saquinavir

Saquinavir, a potent human immunodeficiency virus protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is coadministered with ritonavir, a strong CYP3A4 inhibitor, to boost its exposure. Ketoconazole is a potent CYP3A inhibitor. The objectives of this study were to investigate the effect of ketoconazole on the pharmacokinetics of saquinavir/ritonavir and vice versa using the approved dosage regimens of saquinavir/ritonavir at 1,000/100 mg twice daily and ketoconazole at 200 mg once daily. This was an open-label, randomized two-arm, one-sequence, two-period crossover study in healthy subjects. In study arm 1, 20 subjects received saquinavir/ritonavir treatment alone for 14 days, followed in combination with ketoconazole treatment for 14 days. In arm 2, 12 subjects received ketoconazole treatment for 6 days, followed in combination with saquinavir/ritonavir treatment for 14 days. The pharmacokinetics were assessed on the last day of each treatment (days 14 and 28 in arm 1 and days 6 and 20 in arm 2). The exposures C_max and the area under the concentration-time curve from 0 to 12 h (AUC_0-12) of saquinavir and ritonavir with or without ketoconazole were not substantially altered after 2 weeks of concomitant dosing with ketoconazole. The C_max and AUC_0-12 of ketoconazole, dosed at 200 mg once daily, were increased by 45% (90% confidence interval = 32 to 59%) and 168% (90% confidence interval = 146 to 193%), respectively, after 2 weeks of concomitant dosing with ritonavir-boosted saquinavir (1,000 mg of saquinavir/100 mg of ritonavir given twice daily). The greater exposure to ketoconazole when given in combination with saquinavir/ritonavir was not associated with unacceptable safety or tolerability. No dose adjustment for saquinavir/ritonavir (1,000/100 mg twice daily) is required when coadministered with 200 mg of ketoconazole once daily, and high doses of ketoconazole (>200 mg/day) are not recommended.